Silver oxide formulations

ABSTRACT

Topical formulations for application to exposed body tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. patent applicationSer. No. 13/021,755 filed Feb. 6, 2011, which draws priority from U.K.Patent Application No. GB1101936.1, filed Feb. 4, 2011 both of which areincorporated by reference for all purposes as if fully set forth herein.

This application is also a continuation in part of U.S. patentapplication Ser. No. 12/841,031 filed Jul. 21, 2010, which drawspriority from U.K. Patent Application No. GB1003870.1, filed Mar. 9,2010, and U.S. Provisional Patent Application Ser. No. 61/227,297, filedJul. 21, 2009, all of which are incorporated by reference for allpurposes as if fully set forth herein.

This application is also a continuation in part of U.S. patentapplication Ser. No. 13/981,393, filed Jul. 24, 2013, which is aNational Phase Application of International Patent Application No.PCT/US2012/022220, filed Jan. 23, 2012, which draws priority from U.K.Patent Application No. GB1101193.9, filed Jan. 24, 2011, all of whichapplications are incorporated by reference for all purposes as if fullyset forth herein.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to anti-microbial silver oxideformulations.

Silver and various silver derivatives are known to have anti-microbialproperties. Silver(II) oxide is known to be more effective thansilver(I) oxide. Commercial applications of such products includeimpregnated bandages, mold-free and odor-free textiles, and variouskinds of skin creams. In addition, there exist several oral medicinesthat utilize silver as an active ingredient, including anti-smokinglozenges containing silver acetate (AgC₂H₃O₂), breath mints coated withsilver, and silver nitrate solutions for treating gum disease.

Skin creams containing silver(II) oxide have been reported to beefficacious in treating various medical conditions, including genitalherpes, oral herpes, vaginitis, vaginal yeast infections, foot and nailfungus, burns, warts, and skin infections. These skin formulations arecharacterized by their creaminess and ease of application, which, interalia, enables the polyvalent silver oxide to intimately contact the skinsurface.

Disadvantageously, however, the various forms of silver oxide, andsilver(II) oxide in particular, are dark gray or charcoal gray powders,and are thus extremely hard to hide within white creams used in variouscosmetic or pharmaceutical topical applications. Moreover, the darksilver oxide particles may stain skin and clothing.

Chronic wound care is a critical and growing issue in healthcaresystems. A chronic wound may be defined as a wound that shows no sign ofappreciable healing within 2-3 months. Chronic wounds such as skinulcers are the most common complication of diabetes, which has beentermed a “Silent Epidemic”. Above and beyond their economic burden onhealthcare systems, chronic wounds represent a debilitating problemhaving significant clinical and social ramifications. Chronic wounds maybe non-responsive or poorly responsive to various known treatments.Consequently, such chronic wounds may become severely infected, leadingto gangrene and amputations.

While some advances have been made in the treatment of wounds, bothchronic and acute, we believe there is a need for further improvementsin formulating stable, efficacious topical silver oxide formulations,and the subject matter of the present disclosure and claims is aimed atfulfilling this need.

SUMMARY OF THE INVENTION

According to teachings of the present invention there is provided atopical formulation for application to exposed body tissue, theformulation including a silver oxide and zinc oxide, intimatelydispersed within a carrier medium.

According to another aspect of the present invention there is provided atopical formulation for application to exposed body tissue, theformulation including a silver oxide and zinc oxide, the silver oxideand the zinc oxide intimately dispersed within a carrier medium, whereinthe silver oxide includes, largely includes, predominantly includes, orconsists essentially of a silver(II) oxide.

According to further features in the described preferred embodiments,the formulation contains at least 0.05%, by weight, of the silver oxide,and at least 0.05%, by weight, of the zinc oxide.

According to still further features in the described preferredembodiments, the formulation contains less than 25%, less than 20%, lessthan 15%, less than 12%, less than 10%, or less than 8%, by weight, ofthe zinc oxide.

According to still further features in the described preferredembodiments, a ratio of the zinc oxide to the silver oxide is at least0.5:1, 1:1, 2:1, 3:1, or 6:1, by weight.

According to still further features in the described preferredembodiments, a ratio of the zinc oxide to the silver oxide is less than100:1, 50:1, 20:1, 12:1, 10:1, or 8:1, by weight.

According to still further features in the described preferredembodiments, the formulation contains less than 3%, by weight, of thesilver oxide.

According to still further features in the described preferredembodiments, the formulation contains at least 0.05%, at least 0.10%, atleast 0.2%, or at least 0.25%, by weight, of the silver oxide.

According to still further features in the described preferredembodiments, the carrier medium includes an oleaginous material.

According to still further features in the described preferredembodiments, the oleaginous material includes a wax.

According to still further features in the described preferredembodiments, the oleaginous material includes beeswax.

According to still further features in the described preferredembodiments, the topical formulation further includes a liquid wax estersuch as jojoba oil or hydrogenated jojoba oil.

According to still further features in the described preferredembodiments, the silver oxide and zinc oxide are selected, and thesilver oxide and the zinc oxide are dispersed within the carrier medium,whereby a whiteness of the formulation satisfies an equation:L*≧(L₀*)+2, wherein L₀* is a baseline whiteness value of theformulation, without the zinc oxide, and L* is a whiteness value of theformulation, including the zinc oxide.

According to still further features in the described preferredembodiments, the silver oxide, the zinc oxide, and the carrier mediumare selected, and the silver oxide and the zinc oxide are dispersedwithin the carrier medium, whereby the whiteness value L* is at least75, at least 78, at least 80, at least 82, or at least 84.

According to still further features in the described preferredembodiments, the content of the silver oxide is at least 0.5%, and thesilver oxide, the zinc oxide, and the carrier medium are selected, andthe silver oxide and the zinc oxide are dispersed within the carriermedium, whereby the whiteness value L* of the formulation is at least80, at least 82, or at least 84.

According to still further features in the described preferredembodiments, the content of the silver oxide is at least 1.0%, and thesilver oxide, the zinc oxide, and the carrier medium are selected, andthe silver oxide and the zinc oxide are dispersed within the carriermedium, whereby the whiteness value L* of the formulation is at least72, at least 75, at least 78, at least 80, at least 82, or at least 84.

According to still further features in the described preferredembodiments, the silver oxide, the zinc oxide, and the carrier mediumare selected, and the silver oxide and the zinc oxide are dispersedwithin the carrier medium, whereby the whiteness value L* of theformulation is at least 82 or at least 84.

According to still further features in the described preferredembodiments, the carrier medium includes an aqueous phase.

According to still further features in the described preferredembodiments, the carrier medium is selected whereby the formulation is awater-based cream or lotion.

According to still further features in the described preferredembodiments, the formulation contains zinc oxide within a range of about0.02% to about 25%, by weight, and the silver oxide largely includes asilver (II) oxide, the formulation including at least about 0.02% of thesilver (II) oxide, by weight.

According to still further features in the described preferredembodiments, the formulation contains at least about 0.05% of the silver(II) oxide, and less than about 12%, less than about 10%, less thanabout 8%, or less than about 6% of the zinc oxide, by weight.

According to still further features in the described preferredembodiments, the formulation contains at least 0.05%, by weight, ofsilver(II) oxide, and the ratio of the zinc oxide to the silver(II)oxide is less than 12:1, less than 10:1, less than 8:1, or less than6:1, by weight.

According to still further features in the described preferredembodiments, the formulation further includes any of the materialsdescribed herein, either individually or in combination with any othermaterial, in any structure or form.

According to yet another aspect of the present invention there isprovided a wound dressing including any of the topical formulationsdescribed herein.

According to still further features in the described preferredembodiments, the wound dressing includes an adhesive-containing bandage,a cotton roll bandage, or a getable polymer.

According to yet another aspect of the present invention there isprovided a method of producing a topical formulation for application toexposed body tissue, the formulation including a silver oxide and zincoxide, intimately dispersed within a carrier medium substantially asdescribed herein, the method including any feature described, eitherindividually or in combination with any feature, in any configuration.

According to yet another aspect of the present invention there isprovided a method of effecting a treatment of skin tissue, substantiallyas described herein, the method including any feature described, eitherindividually or in combination with any feature, in any configuration.

According to further features in the described preferred embodiments,the method includes the steps of: (a) providing a formulation including:(i) a silver oxide such as a silver(II) oxide; (ii) zinc oxide, and(iii) a carrier medium, wherein the formulation contains at least 0.05%,by weight, of the silver oxide, and less than 25%, less than 20%, lessthan 15%, less than 12%, less than 10%, or less than 8% of the zincoxide by weight, of the zinc oxide, and wherein the silver oxide and thezinc oxide are intimately dispersed within the carrier medium, and (b)applying the formulation to the skin tissue to effect the treatment ofthe skin tissue.

According to another aspect of the present invention there is provided atopical formulation for application to exposed body tissue, theformulation including: (a) a silver oxide, and (b) at least oneinorganic whitener; selected from the group of inorganic whitenersconsisting of an inorganic magnesium compound and an inorganic calciumcompound, the silver oxide and the inorganic whitener compoundintimately dispersed within a carrier medium, and wherein a ratio of theinorganic whitener compound, to the silver oxide, is at least 0.2:1, byweight, within the formulation.

According to another aspect of the present invention there is provided atopical formulation for application to exposed body tissue, theformulation including: (a) a silver oxide; and (b) at least oneinorganic whitener; wherein a ratio of the inorganic whitener compound,to the silver oxide, is at least 0.2:1, by weight, within theformulation.

According to further features in the described preferred embodiments,the initial whiteness value of the formulation is at least 4 reflectiveunits.

According to still further features in the described preferredembodiments, the whiteness value of the formulation is, initially, atleast 4 reflective units, at least 4.5 reflective units, at least 5reflective units, at least 5.5 reflective units, or at least 6reflective units, and wherein, after constant exposure to theultraviolet light for 3 days, the value remains at least 3.5 reflectiveunits, at least 3.75 reflective units, at least 4 reflective units, atleast 4.5 reflective units, at least 5 reflective units, or at least 5.5reflective units.

According to still further features in the described preferredembodiments, the initial whiteness value of the formulation is at least4 reflective units, at least 4.5 reflective units, at least 5 reflectiveunits, at least 5.5 reflective units, or at least 6 reflective units,and wherein, after constant exposure to the ultraviolet light for 3days, a whiteness value of the formulation remains within 1.5 reflectiveunits, within 1.25 reflective units, or within 1.0 reflective units ofthe initial whiteness value.

According to still further features in the described preferredembodiments, the formulation contains at least 0.05%, at least 0.10%, atleast 0.2%, at least 0.25%, at least 0.30%, at least 0.50%, at least0.75%, or at least 1%, by weight, of the silver(I) oxide and/orsilver(II) oxide.

According to still further features in the described preferredembodiments, the formulation contains less than 3%, by weight, of thesilver oxide.

According to still further features in the described preferredembodiments, the whitener is further selected to act as a stabilizationagent that partially inhibits a darkening of the formulation when theformulation is exposed to ultraviolet light.

According to still further features in the described preferredembodiments, the formulation has a gray or light gray hue.

According to still further features in the described preferredembodiments, the carrier medium includes an oleaginous material.

According to still further features in the described preferredembodiments, the oleaginous material includes a wax.

According to still further features in the described preferredembodiments, the oleaginous material includes beeswax.

According to still further features in the described preferredembodiments, the carrier medium includes a liquid wax ester.

According to still further features in the described preferredembodiments, the liquid wax ester includes, predominantly includes, orconsists essentially of jojoba oil.

According to still further features in the described preferredembodiments, the carrier medium includes a hydrogenated liquid waxester.

According to still further features in the described preferredembodiments, the liquid wax ester includes, predominantly includes, orconsists essentially of hydrogenated jojoba oil.

According to still further features in the described preferredembodiments, the whitener is an inorganic powder.

According to still further features in the described preferredembodiments, the topical formulation further includes zinc oxide.

According to still further features in the described preferredembodiments, the whitener is further selected to act as a stabilizationagent that partially inhibits a darkening of the formulation when theformulation is exposed to ultraviolet light.

According to still further features in the described preferredembodiments, the formulation contains at least 0.02%, at least 0.1%, atleast 0.5%, at least 1%, at least 1.5%, at least 2%, at least 3%, atleast 5%, or at least 7%, by weight, of the zinc oxide.

According to still further features in the described preferredembodiments, the formulation further includes a stabilization agentselected to partially inhibit a darkening of the formulation whenexposed to ultraviolet light.

According to still further features in the described preferredembodiments, the whitener and the stabilization agent have a totalconcentration of at least about 0.01%, by weight, and the silver oxidehas a concentration of at least about 0.01%, by weight.

According to still further features in the described preferredembodiments, the silver oxide includes, largely includes, mainlyincludes, predominantly includes, or consists essentially of asilver(II) oxide.

According to still further features in the described preferredembodiments, the silver oxide includes, largely includes, mainlyincludes, predominantly includes, or consists essentially of a silver(I)oxide.

According to still further features in the described preferredembodiments, the ratio of the stabilization agent to the zinc oxide,within the formulation, is at least 0.5:1, at least 1:1, at least 1.5:1,at least 2:1, at least 3:1, at least 5:1, or at least 7:1, by weight,the stabilization agent selected to partially inhibit a darkening of theformulation when the formulation is exposed to ultraviolet light.

According to still further features in the described preferredembodiments, the stabilization agent is selected from the groupconsisting of bentonite, magnesium hydroxide, calcium hydroxide, calciumcarbonate, magnesium oxide, magnesium carbonate, and magnesium sulfate.

According to still further features in the described preferredembodiments, the formulation contains between 0.02% and 10% of the zincoxide, and between 0.01% and 30% of the stabilization agent.

According to still further features in the described preferredembodiments, the inorganic whitener includes at least one inorganicwhitener selected from the group consisting of magnesium oxide,magnesium hydroxide, and magnesium carbonate.

According to still further features in the described preferredembodiments, the stabilization agent includes magnesium oxide.

According to still further features in the described preferredembodiments, the formulation contains less than 0.5%, less than 0.3%, orless than 0.1% titanium dioxide, or is substantially free of thetitanium dioxide.

According to still further features in the described preferredembodiments, the topical formulation further includes zinc oxide, butcontains less than 0.5%, less than 0.3%, or less than 0.1% thereof, andthe ratio of the stabilization agent, the whitener, and the zinc oxide,to the silver oxide, is at least 0.5:1, at least 0.75:1, at least 1:1,at least 1.5:1, at least 2:1, at least 3:1, or at least 5:1, by weight,within the formulation.

According to still further features in the described preferredembodiments, the ratio of the stabilization agent, the whitener, and thezinc oxide, to the silver oxide, is at least 0.5:1, at least 0.75:1, atleast 1:1, at least 1.5:1, at least 2:1, at least 3:1, or at least 5:1,by weight, within the formulation.

According to still further features in the described preferredembodiments, the total concentration of the whitener and thestabilization agent is at least 0.01%, at least 0.05%, at least 0.1%, atleast 0.5%, at least 1%, at least 2%, at least 3%, at least 5%, at least7%, or at least 10%.

According to still further features in the described preferredembodiments, the inorganic magnesium compound is selected from the groupconsisting of a magnesium oxide, a magnesium carbonate, and a magnesiumsulfate.

According to still further features in the described preferredembodiments, the inorganic calcium compound is selected from the groupconsisting of a calcium oxide, a calcium carbonate, and a calciumsulfate.

According to still further features in the described preferredembodiments, the silver oxide has a dark hue.

According to still further features in the described preferredembodiments, the silver oxide has a hue within a range of shades betweengray and black.

According to still further features in the described preferredembodiments, the formulation has a hue that is lighter than the hue ofthe silver oxide.

According to still further features in the described preferredembodiments, the formulation has a hue that is lighter than the hue ofthe silver oxide, after the formulation is subject to constant exposureto ultraviolet light for at least 3 days.

According to another aspect of the present invention there is provided asolid biocompatible formulation suitable for insertion within chronicand acute wounds of humans and animals, the formulation including atopical antibiotic, a biocompatible humectant, and a biocompatibleviscosity-building agent, the humectant and the viscosity-building agentintimately mixed within the formulation, which is formulated and adaptedwhereby the formulation remains a solid over at least an entiretemperature range of 20° C. to 35° C., the solid formulation having astorage modulus (G′) and a loss modulus (G″), both measured at 25° C.and within a frequency range of 0.1 Hz to 1.0 Hz, and a complex modulus(G*), defined by:G*=(G′ ² +G″ ²)^(1/2)

the formulation having at least one of the following five rheologicalproperties:

(1) in a torque sweep at a frequency of 1.0 Hz, the complex modulusachieves a plateau or a maximum of at least 4.0×10⁴ Pa, at least 6.0×10⁴Pa, at least 8.0×10⁴ Pa, or at least 10.0×10⁴ Pa;

(2) in the torque sweep, the complex modulus drops sharply, or begins toexhibit non-linear behavior, at an oscillating stress of at least 800Pa, at least 900 Pa, at least 1000 Pa, at least 1200 Pa, at least 1500Pa, or at least 2000 Pa;

within the frequency range, at at least one point:

(3) the storage modulus is at least 1.0×10⁴ Pa, at least 2.0×10⁴ Pa, atleast 3.0×10⁴ Pa, at least 4.0×10⁴ Pa, at least 5.0×10⁴ Pa, or at least6.0×10⁴ Pa;

(4) the loss modulus is at least 0.4×10⁴ Pa, at least 0.5×10⁴ Pa, atleast 0.6×10⁴ Pa, at least 0.8×10⁴ Pa, at least 1.0×10⁴ Pa, at least1.5×10⁴ Pa or at least 2.0×10⁴ Pa;

(5) the complex modulus is at least 1.05×10⁴ Pa, at least 1.05×10⁴ Pa,at least 2×10⁴ Pa, at least 3.0×10⁴ Pa, at least 4.0×10⁴ Pa, or at least6.0×10⁴ Pa.

According to further features in the described preferred embodiments,the complex modulus achieves a plateau or maximum of at least 4.0×10⁴Pa, at least 6.0×10⁴ Pa, at least 8.0×10⁴ Pa, or at least 10.0×10⁴ Pa.

According to still further features in the described preferredembodiments, the complex modulus drops sharply, or begins to exhibitnon-linear behavior, at an oscillating stress of at least 800 Pa, atleast 900 Pa, at least 1000 Pa, at least 1200 Pa, at least 1500 Pa, orat least 2000 Pa.

According to still further features in the described preferredembodiments, at at least one point within the frequency range, thestorage modulus is less than 1.2×10⁷ Pa, less than 1.0×10⁷ Pa, less than8×10⁶ Pa, or less than 7×10⁶ Pa.

According to still further features in the described preferredembodiments, at at least one point within the frequency range, the lossmodulus is less than 5×10⁶ Pa, less than 3×10⁶ Pa, less than 2×10⁶ Pa,or less than 1×10⁶ Pa.

According to still further features in the described preferredembodiments, at at least one point within the frequency range, thecomplex modulus is less than 1.2×10⁷ Pa, less than 1.0×10⁷ Pa, less than8×10⁶ Pa, or less than 7×10⁶ Pa.

According to still further features in the described preferredembodiments, at at least one point within the frequency range, a ratioof the storage modulus to the loss modulus is at least 1.5:1, at least2.0:1, at least 2.5:1, at least 3:1, at least 4:1, or at least 5:1,and/or the ratio is less than 12:1, less than 10:1, less than 9:1, orless than 8:1.

According to still further features in the described preferredembodiments, at at least one point within the frequency range, thestorage modulus is at least 3.0×10⁴ Pa, at least 4.0×10⁴ Pa, at least5.0×10⁴ Pa, or at least 6.0×10⁴ Pa, and the loss modulus is at least0.6×10⁴ Pa, at least 0.8×10⁴ Pa, at least 1.0×10⁴ Pa, at least 1.5×10⁴Pa, or at least 2.0×10⁴ Pa.

According to still further features in the described preferredembodiments, at at least one point within the frequency range, thestorage modulus is at least 5.0×10⁴ Pa, or at least 6.0×10⁴ Pa, and theloss modulus is at least 0.8×10⁴ Pa, at least 1.0×10⁴ Pa, at least1.5×10⁴ Pa, or at least 2.0×10⁴ Pa.

According to still further features in the described preferredembodiments, a ratio of the storage modulus to the loss modulus is atleast 1.5:1, at least 2.0:1, at least 2.5:1, at least 3:1, at least 4:1,or at least 5:1, and/or the ratio is less than 12:1, less than 10:1,less than 9:1, or less than 8:1, substantially throughout the frequencyrange.

According to still further features in the described preferredembodiments, the storage modulus is at least 3.0×10⁴ Pa, at least4.0×10⁴ Pa, at least 5.0×10⁴ Pa, or at least 6.0×10⁴ Pa, substantiallythroughout the frequency range.

According to still further features in the described preferredembodiments, the loss modulus is at least 0.6×10⁴ Pa, at least 0.8×10⁴Pa, at least 1.0×10⁴ Pa, at least 1.5×10⁴ Pa, or at least 2.0×10⁴ Pa,substantially throughout the frequency range.

According to still further features in the described preferredembodiments, the storage modulus is at least 5.0×10⁴ Pa, or at least6.0×10⁴ Pa, substantially throughout the frequency range.

According to still further features in the described preferredembodiments, the loss modulus is at least 1.0×10⁴ Pa, at least 1.5×10⁴Pa, or at least 2.0×10⁴ Pa, substantially throughout the frequencyrange.

According to still further features in the described preferredembodiments, the water concentration within the formulation is at least5%, at least 7%, at least 10%, at least 20%, at least 30%, at least 40%,at least 50%, or at least 60%.

According to still further features in the described preferredembodiments, the concentration of the antibiotic within the formulationis at least 0.1%, at least 0.2%, at least 0.4%, at least 0.7%, or atleast 1%.

According to still further features in the described preferredembodiments, the antibiotic is present within the formulation in atherapeutically effective concentration for treatment of topical skininfections.

According to still further features in the described preferredembodiments, the antibiotic is selected from the group of topicalantibiotics consisting of silver(II) oxide, silver(I) oxide, silversulfadiazine, Bacitracin, Neomycin, Erythromycin and Chloramphenicol.

According to still further features in the described preferredembodiments, the humectant and the viscosity-building agent areselected, and the formulation is adapted, whereby a melting temperatureof the formulation is at least 40° C., at least 45° C., at least 50° C.,or at least 75° C.

According to still further features in the described preferredembodiments, the formulation is a putty at 20° C. or at 22° C., at 35°C. or at 37° C., or throughout the temperature range.

According to still further features in the described preferredembodiments, the formulation contains at least 1%, at least 1.5%, atleast 2.5%, at least 3%, at least 4%, at least 7%, at least 12%, atleast 20%, or at least 30% of the humectant.

According to still further features in the described preferredembodiments, the formulation contains less than about 55%, less than50%, less than 48%, less than 45%, or less than 40%, of the humectant.

According to still further features in the described preferredembodiments, the humectant includes, largely includes, predominantlyincludes, or consists essentially of a liquid wax ester.

According to still further features in the described preferredembodiments, the formulation further includes an absorbefacient.

According to still further features in the described preferredembodiments, the formulation further includes an absorbefacient, whereina combined weight content of the viscosity-building agent and theabsorbefacient within the formulation is at least about 4%, at least 6%,at least 8%, at least 10%, or at least 15%.

According to still further features in the described preferredembodiments, the combined weight content is in a range of about 8% to70%, about 8% to 65%, or about 10% to 50%.

According to still further features in the described preferredembodiments, the viscosity-building agent includes, largely includes, orconsists essentially of at least one of a hydrophilic clay, a flour, anda starch.

According to still further features in the described preferredembodiments, the absorbefacient includes, largely includes, or consistsessentially of at least one of a hydrophilic clay, a flour, and astarch.

According to still further features in the described preferredembodiments, the hydrophilic clay is selected from at least one of thegroup of hydrophilic clays consisting of a smectite, sepiolite, andpalygorskite.

According to still further features in the described preferredembodiments, the smectite is selected from at least one of the groupconsisting of bentonite, montmorillonite and hectorite.

According to still further features in the described preferredembodiments, a weight ratio of the at least one viscosity-building agentand absorbefacient to humectant is at least 0.25:1, at least 0.4:1, atleast 0.6:1, at least 1:1, and more typically, about 1.5:1 to 5:1, about2:1 to 5:1, or about 2:1 to 4:1.

According to still further features in the described preferredembodiments, the humectant includes jojoba oil, hydrogenated jojoba oil.

According to still further features in the described preferredembodiments, the humectant includes, largely includes, or consistsessentially of jojoba oil.

According to still further features in the described preferredembodiments, the formulation further includes at least 0.3%, at least1%, at least 2.5%, or at least 4% of a skin-protecting agent.

According to still further features in the described preferredembodiments, the skin-protecting agent includes zinc oxide.

According to still further features in the described preferredembodiments, the formulation contains, by weight, less than 15%, lessthan 12%, or less than 10% of the skin-protecting agent.

According to still further features in the described preferredembodiments, the formulation is an elastic, moldable formulation.

According to still further features in the described preferredembodiments, the formulation is adapted whereby a plug or piece of theformulation may be fit to a contour of a wound cavity.

According to still further features in the described preferredembodiments, the formulation is adapted whereby a plug or piece of theformulation may be inserted into a wound cavity in an integral fashion.

According to still further features in the described preferredembodiments, the formulation is adapted wherein a plug or piece of theformulation securely holds position within a wound cavity.

According to still further features in the described preferredembodiments, the formulation and/or a plug or piece of the formulationis adapted to be removed from a wound cavity in an integral fashion.

According to still further features in the described preferredembodiments, the formulation and/or a plug or piece of the formulationis adapted to provide a gentle pressure against a surface within a woundcavity.

According to still further features in the described preferredembodiments, the formulation and/or a plug or piece of the formulationis adapted to be removed from the wound cavity in an integral fashion,after contacting the surface for at least 4 hours, at least 12 hours, orat least 24 hours.

According to yet another aspect of the present invention there isprovided a formulation suitable for application to skin tissue,substantially as described herein, the formulation including any featuredescribed, either individually or in combination with any feature, inany configuration.

According to another aspect of the present invention there is provided amethod of producing a composition, formulation, or medical device, themethod including any feature described, either individually or incombination with any feature, in any configuration.

According to another aspect of the present invention there is provided amethod of topically applying the inventive formulation or medical deviceon the skin, on a wound, or within a wound cavity, the method includingany feature described, either individually or in combination with anyfeature, in any configuration.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice. Throughout thedrawings, like-referenced characters are used to designate likeelements.

In the drawings:

FIG. 1 is a graph plotting whiteness of cloth swatches stained withformulations containing varying concentrations zinc oxide and silver(II)oxide, as a function of the weight content of zinc oxide within theformulations;

FIG. 2 is a graph plotting whiteness of the cloth swatches as a functionof the weight ratio of zinc oxide to silver(II) oxide within each of theabove formulations;

FIG. 3 is a graph plotting whiteness of laundered cloth swatches as afunction of the weight content of zinc oxide in the stainingformulations initially applied to the swatches;

FIG. 4 is a graph plotting whiteness of the laundered cloth swatches asa function of the weight ratio of zinc oxide to silver(II) oxide withinthe staining formulations initially applied to the swatches;

FIG. 5 provides top view photographs of Petri dishes containingoil-based formulations and identically grown cultures according to amodified pour plate method, wherein:

FIG. 5A shows a cultured Petri dish after being exposed to a formulationcontaining 1.0% AgO and 7.0% ZnO;

FIG. 5B shows a cultured Petri dish after being exposed to a formulationcontaining 1.0% AgO and no ZnO;

FIG. 5C shows a cultured Petri dish after being exposed to a formulationcontaining 7.0% ZnO and no AgO;

FIG. 5D shows a cultured Petri dish after being exposed to a formulationcontaining 1.0% AgO and 14.0% ZnO;

FIG. 5E shows a cultured Petri dish after being exposed to a formulationcontaining 0.84% AgO and 28.0% ZnO;

FIG. 6 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for formulations containing AgO (1%)and Ag₂O (1%), respectively, in a carrier base;

FIG. 6A is a graph plotting reflectance, as a function of the exposuretime to ultraviolet light, for three formulations containing AgO (1%) invarious carrier bases;

FIG. 7 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for the AgO formulation of FIG. 6,versus similar formulations containing AgO along with the inorganicwhiteners TiO₂, and ZnO, respectively;

FIG. 8 provides a graph plotting formulation whiteness, as a function ofthe exposure time to ultraviolet light, for the formulations of FIG. 7,versus similar formulations containing AgO along with the inorganicsubstances bentonite, CaCO₃, Ca(OH)₂ and MgSO₄, respectively;

FIG. 8A presents a graph plotting normalized formulation whiteness(whiteness equals 1 at t=0), as a function of the exposure time toultraviolet light, for the formulations of FIG. 8;

FIG. 8B is a graph plotting the absolute decrease in formulationreflectance (in RU) as a function of the exposure time to ultravioletlight, for the formulations of FIG. 8;

FIG. 9 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for the formulations of FIG. 7,versus similar formulations containing AgO along with the inorganicsubstances Mg(OH)₂, MgCO₃, and MgO, respectively;

FIG. 9A provides a graph plotting normalized formulation reflectance orwhiteness (WN) as a function of the exposure time to ultraviolet light,for the formulations of FIG. 9;

FIG. 9B presents a graph plotting the absolute decrease in formulationreflectance as a function of the exposure time to ultraviolet light, forthe formulations of FIG. 9;

FIG. 10 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, showing the whiteness stabilizationperformance of various inorganic substances in formulations containingAgO and ZnO;

FIG. 10A is a graph comparing formulation whiteness of variousformulations of FIG. 10, with the formulation whiteness of substantiallyidentical formulations having different carrier base compositions, as afunction of the exposure time to ultraviolet light;

FIG. 11 is a graph plotting the whiteness behavior of various AgO basedformulations and the whiteness behavior of various Ag₂O basedformulations, as a function of the exposure time to ultraviolet light;

FIG. 11A presents a graph plotting normalized formulation reflectance(WN) as a function of the exposure time to ultraviolet light, for silveroxide formulations (1% by weight) having different carrier bases;

FIG. 12 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, showing the whiteness stabilizationperformance of various inorganic substances in formulations containingAg₂O and ZnO;

FIGS. 13A-13C are photographs of a cloth stained with formulations ofthe present invention, after 3 days, 10 days, and 21 days of constantexposure to ultraviolet light;

FIG. 14 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for formulations containing AgO andvarying concentrations of MgO, versus similar formulations containingsolely AgO, and AgO and ZnO;

FIG. 14A presents a magnified, partial view of the graph of FIG. 14,showing exposure times of up to 3 days;

FIG. 14B provides a graph plotting normalized formulation whiteness (WN)as a function of the exposure time to ultraviolet light, for theformulations of FIG. 14A;

FIG. 15 is a bar graph showing the turbidity of a plurality of cultures,each culture containing a particular anti-microbial formulation;

FIG. 16 is a bar graph showing the colony counts for the anti-microbialformulation containing cultures of FIG. 15;

FIG. 17 provides a plot of the storage modulus G′ and the loss modulusG″, as a function of frequency, for a first formulation of the presentinvention;

FIG. 18 provides a plot of the storage modulus G′ and the loss modulusG″, as a function of frequency, for a second formulation of the presentinvention;

FIG. 19 shows a torque sweep as a function of the oscillating stress,for a third formulation of the present invention;

FIG. 20 provides a plot of the storage modulus G′ and the loss modulusG″, as a function of frequency, for the formulation of FIG. 19;

FIG. 21 provides bar graphs of the zones of inhibition of variousformulation of the present invention; and

FIG. 22 provides bar graphs showing clinical wound closure data fromcomparative clinical trials in which the use of an exemplary putty ofthe present invention is tested against the use of a silver oxideointment and against a conventional treatment protocol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description. The invention may be capable ofother embodiments or of being practiced or carried out in various ways.Also, it is to be understood that the phraseology and terminologyemployed herein is for the purpose of description and should not beregarded as limiting.

The medical device of the present invention contains both a silver oxidecompound and zinc oxide, preferably in a carrier medium that may be awater-based cream or lotion, or an ointment that may include a waxand/or an oil. The formulation may include an emulsion, or besubstantially emulsion-based.

The inventive silver oxide based medical device may have a generallywhite appearance. At lower ratios of whitening agent to silver oxide,the appearance of the medical device may be off-white or grayish.

We have found that silver(II) oxide, despite being an extremely reactivematerial, does not deleteriously interact with zinc oxide within theformulation. We have also found that the zinc oxide does not appear toreduce or appreciably reduce the anti-microbial efficacy of thesilver(II) oxide. This appears to be particularly surprising, becausezinc oxide is used in various coating applications, and might beexpected to cover or block the silver(II) oxide particles, therebyreducing the contact between the silver(II) oxide particles and themicroorganisms.

Moreover, we have surprisingly discovered that within a specified rangeof weight ratios and/or compositions, the silver oxide based formulationis highly spreadable, despite the presence of the chalky zinc oxide. Wehave found that silver oxide-zinc oxide formulations containing morethan 25% zinc oxide, by weight, may display poor spreadability, and mayalso be less efficacious from an anti-microbial standpoint. In someformulations, a zinc oxide content of more than 20%, by weight, mayexhibit such deleterious properties.

We have found that for formulations within a particular range of zincoxide to silver oxide weight ratios, or having a particular range ofzinc oxide and silver oxide contents, the zinc oxide acts to appreciablywhiten the inventive formulations. However, above this particular rangeof zinc oxide to silver oxide weight ratios, or above a particularamount of zinc oxide, the whitening effect of the zinc oxide may becomesubstantially insignificant.

Whiter formulations tend to be more aesthetically pleasing, and it wouldappear that such whiter formulations would tend to promote less stainingof fabric such as clothes. However, we have surprisingly found that whenformulations containing zinc oxide mixed with a silver oxide (such as asilver(II) oxide) are disposed on a fabric, conventional laundering ofthe fabric yields stains having a lightness that may not monotonicallycorrelate with the lightness of the initial stain, prior to thelaundering.

With reference now to FIG. 1, FIG. 1 is a graph plotting formulationwhiteness or luminance (expressed as L*) as a function of zinc oxideconcentration (in weight percent) within the formulation. The whitenessparameter L* has been specified by the International Commission onIllumination (Commission Internationale d'Eclairage, or CIE) to achieveperceptual uniformity, and the L* component thereof has been determinedto closely match human perception of lightness. Regarding the scale ofL*, the luminance is expressed as a percentage, wherein L*=0 representsblack, and L*=100 represents diffuse white.

In FIG. 1, formulations containing three concentrations of silver(II)oxide were tested: 0.25%, 0.5%, and 1%, by weight, respectively. As maybe seen from the data in Table 1 and from FIG. 1, the formulationwhiteness (L*) increases substantially monotonically with increasingconcentration of zinc oxide. However, appreciable differential increasesin the formulation whiteness (L*) are typically obtained when the zincoxide concentration is less than about 12%, less than about 10%, lessthan about 8%, or less than about 6% zinc oxide, by weight.

TABLE 1 % zinc oxide L* 0.25% silver(II) oxide 0 81.16 0.25 81.81 0.7584.58 1.5 85.11 3 85.84 5 87.12 0.5% silver(II) oxide 0 76.62 0.5 81.391.5 80.04 3 83.65 6 85.17 10 86.73 1% silver(II) oxide 0 68.89 1 71.34 376.20 6 77.51 12 83.98 20 85.09

FIG. 2 is a graph plotting formulation whiteness (expressed as L*) as afunction of the weight ratio of zinc oxide to silver(II) oxide withineach formulation.

As may be seen from the data in Table 2 and from FIG. 2, the formulationwhiteness (L*) increases substantially monotonically with increasingratio of zinc oxide to silver(II) oxide. However, appreciabledifferential increases in the formulation whiteness (L*) are typicallyobtained when the ratio of zinc oxide to silver(II) oxide within theformulation is less than about 15:1, less than about 12:1, less thanabout 10:1, less than about 8:1, or less than about 6:1. Below a ratioof about 20:1, the differential increase in the formulation whiteness isless substantial.

We have surprisingly found that when formulations containing zinc oxidemixed with a silver oxide (such as a silver(II) oxide) are disposed on afabric, conventional laundering of the fabric yields stains that may notmonotonically correlate with the lightness of the initial stain, priorto the laundering. Table 3 provides whiteness (L*) as a function ofconcentration of zinc oxide, for a white fabric impregnated with theformulations provided in Table 1, after the fabric has undergone astaining and laundering procedure.

TABLE 2 ratio of ZnO to silver(II) oxide L* 0.25% silver(II) oxide 081.16 0.25 81.81 0.75 84.58 1.5 85.11 3 85.84 5 87.12 0.5% silver(II)oxide 0 76.62 0.5 81.39 1.5 80.04 3 83.65 6 85.17 10 86.73 1% silver(II)oxide 0 68.89 1 71.34 3 76.20 6 77.51 12 83.98 20 85.09

The following procedure was used:

Cut a 7×7 cm piece of fabric from a white cotton T-shirt to produce acloth swatch;

-   -   1. Weigh the cloth swatch;    -   2. Place cloth swatch on a clean paper towel to absorb any        extraneous oil from the staining procedure;    -   3. Apply 400 mg of staining sample to the back of spatula;    -   4. Spread sample evenly over 90% of cloth surface using spatula,        taking care        -   a. not to stain edges, and        -   b. to use the entire staining sample;    -   5. Re-weigh cloth swatch to insure complete transfer of the        sample (typically weighs an additional ˜400 mg);    -   6. Allow the cloth to absorb the sample for 24 hours in an open        air environment at room temperature (65-75° F.);    -   7. Place cloth in 650-700 ml of warm detergent/water solution        (regular tap water and Lestoil® brand detergent/stain remover or        similar);        -   a. Solution is prepared using 10 ml of detergent for every            liter of water;        -   b. Solution is drawn anew from a stock solution for each            sample;        -   c. Stock solution is warmed to ˜130° F.;    -   8. Mix cloth-containing solution for 10 minutes using mixer        operating at 300 rpm;    -   9. Rinse cloth by placing in beaker of clean water. Remove        cloth, and repeat rinsing procedure for a total of three rinses,        each time using new clean water;    -   10. Pin swatches to uniform flat wall;        -   a. Pin only the unstained edges;        -   b. Place in open air environment;        -   c. Maintain swatches at room temperature (65-75° F.); and    -   11. Store swatches in a lightproof pouch until ready to measure        with colorimetric instrument.

The whiteness of the various samples was measured using a Color Cue® 2.1colorimetric instrument (Pantone, Inc.). A clear plastic wrap was placedover each sample. The colorimeter was then lightly pressed onto the wrapand the color was recorded. The L* reading was used to indicate therelative lightness of the stain with respect to other samples. Readingswere recorded from 3 separate areas on the cloth sample, and theobtained values were averaged.

The formulations used in the staining and laundering procedure containedthree concentrations of silver(II) oxide: 0.25%, 0.5%, and 1%, byweight, as described with respect to Table 1 hereinabove. With referencenow to the values provided in Table 3, and plotted in FIG. 3, it isobserved that at low zinc oxide content, the whiteness (L*) of thelaundered cloth swatches increases with increasing concentration of zincoxide. However, at each of the three concentrations of silver oxide, amaximum whiteness is observed at zinc oxide contents of about 0.75%,1.5%, and 6%, respectively. Above these values, the whiteness (L*) ofthe laundered cloth swatches levels off, or may even decrease somewhatwith increasing concentration of zinc oxide.

The presently preferred zinc oxide content in the formulations of thepresent invention may be heavily dependent on the silver oxide contentwithin the formulation, which may be at least 0.05%, at least 0.1%, atleast 0.25%, at least 0.5%, at least 0.75%, at least 1%, or at least 3%,by weight. However, the preferred zinc oxide content may depend upon theparticular composition of the formulation, upon the composition of thebase material(s), and upon other formulation characteristics. Generally,however, the presently preferred zinc oxide content in the formulationsof the present invention may be at least 0.5%, at least 0.75%, at least1%, or at least 3%, by weight. The presently preferred zinc oxidecontent in the formulations of the present invention may be less than20%, by weight, and more typically, less than about 12%, less than about10%, less than about 8% zinc oxide, or less than about 6% zinc oxide.

TABLE 3 % zinc oxide L* 0.25% silver(II) oxide 0 84.38 0.25 86.96 0.7587.66 1.5 87.18 3 86.67 5 86.95 0.5% silver(II) oxide 0 80.52 0.5 83.311.5 83.96 3 83.19 6 83.73 10 83.22 1% silver(II) oxide 0 71.39 1 73.81 374.85 6 77.38 12 77.17 20 75.64

FIG. 4 is a graph plotting formula whiteness (expressed as L*) as afunction of the weight ratio of zinc oxide to silver(II) oxide withineach formulation used in the staining and laundering procedure describedhereinabove. As may be seen from FIG. 4 and the corresponding data inTable 4, the formulation whiteness (L*) generally increases appreciablywith increasing ratio of zinc oxide to silver(II) oxide, at low weightratios of zinc oxide to silver(II) oxide. Surprisingly, however, above aweight ratio of zinc oxide to silver(II) oxide of 1:1, 3:1, 5:1, or 6:1,the formulation whiteness generally increases only marginally, or failsto increase, with increasing ratio of zinc oxide to silver(II) oxide.Indeed, above a weight ratio of zinc oxide to silver(II) oxide of 8:1,10:1, or perhaps most clearly, 12:1, the formulation whiteness may besubstantially constant, or may even decrease with increasing ratio ofzinc oxide to silver(II) oxide.

TABLE 4 ratio of ZnO to silver(II) oxide L* 0.25% silver(II) oxide 084.38 1 86.96 3 87.66 6 87.18 12 86.67 20 86.95 0.5% silver(II) oxide 080.52 1 83.31 3 83.96 6 83.19 12 83.73 20 83.22 1% silver(II) oxide 071.39 1 73.81 3 74.85 6 77.38 12 77.17 20 75.64

Thus, the general appearance of the curve of the stained and launderedsamples does not parallel or closely follow the general appearance ofthe curve of the stained samples. Moreover, at high zinc oxide contentsor zinc oxide to silver(II) oxide ratios, the formulation whitenessappears to decrease with increasing zinc oxide content or ratio, insteadof continuing to increase, as in the stained samples. Without wishing tobe limited by theory, I attribute this to the tendency of the zinc oxideparticles to adhere to the fabric, compounded by the tendency of thesilver(II) oxide particles to adhere to, or otherwise associate with,the zinc oxide particles. Even so, the zinc oxide does not appear toreduce or appreciably reduce the anti-microbial efficacy of thesilver(II) oxide.

An exemplary general procedure for producing the inventive silver oxidebased cream is as follows: a liquid wax ester such as jojoba oil orhydrogenated jojoba oil is heated, preferably to around 80° C. A waxsuch as beeswax is preferably melted into the liquid wax ester. Thematerial is mixed thoroughly as it is cooled below about 60° C. Anessential oil such as palmarosa oil may be added. Mixing is continued aszinc oxide is introduced along with a silver oxide such as a silver (II)oxide or a silver (I) oxide, and the mixing may be continued duringcooling of the mixture to below about 40° C. The mixing mayadvantageously produce an intimately dispersed formulation in which thesilver oxide and/or the zinc oxide may be distributed in a homogeneousor substantially homogeneous fashion within the carrier medium.

Typically, the formulations contain 0.05% to 3% silver oxide, by weight,and more typically, 0.1% to 3% silver oxide. The formulations alsocontain 1% to 22% zinc oxide, by weight, and more typically, 1% to 20%zinc oxide.

EXAMPLES

Reference is now made to the following examples, which together with theabove description, illustrate the invention in a non-limiting fashion.

Example 1

The exemplary silver oxide-zinc oxide formulations provided hereinbelowwere prepared according to the following general procedure: jojoba oilis heated to 80° C. A wax such as beeswax may then be introduced. Thematerial is mixed thoroughly as it is cooled to about 55° C. Palmarosaoil is added, followed by silver (II) oxide and zinc oxide. Mixing maybe maintained throughout, and during cooling of the mixture to 35°C.-40° C.

In these exemplary formulations, the weight ratio of the liquid waxester to beeswax is about 3.5 to 1. The palmarosa oil content is about0.07% of the jojoba oil content.

Examples 2-13

Using the general procedure provided in Example 1, various silveroxide-zinc oxide formulations were prepared. Some of the specificformulations are provided below, by way of example, in Table 5.Formulations that have not been provided below produced qualitativelysimilar results. The percentages of silver oxide and zinc oxide are byweight, based on the total weight of the final product.

Visual whiteness evaluations were performed on each of the samples,using the scale provided in Table 6.

Example 14

The exemplary silver oxide-zinc oxide formulations provided hereinbelowwere prepared according to the following general procedure: to acontainer containing water is added a viscosity-building agent,typically a smectite (e.g., a bentonite or montmorillonite powder suchas Gelwhite H, produced by Southern Clay Products, Inc., Gonzales,Tex.). Other viscosity-building clays, particularly clays in which thesilicate layers are disposed in a sandwiched structure, may also beused. Other viscosity-building agents and thickeners may be used, e.g.,glycerin and carbomers. Preferably, such selected materials may exhibitgood resistance to oxidation or chemical attack by the highly reactivesilver(II) oxide.

The mixture is mixed or homogenized, typically for 0.5 to 2 hours.Silver(II) oxide may be introduced at this stage of the processing Zincoxide may be introduced to the mixture, typically along with thesilver(II) oxide, or sometime therebefore or thereafter. The oil and/orliquid wax ester (e.g., jojoba oil) may be introduced to the mixtureduring the mixing (e.g., blending or homogenizing).

TABLE 5 Silver Zinc Oxide Oxide Wt. Ratio Whiteness SpreadabilityExample 2 1.00% 3.00% 1 to 3  4 Excellent Example 3 0.50% 3.00% 1 to 6 6 Excellent Example 4 0.25% 3.00% 1 to 12 8 Excellent Example 5 1.00%7.00% 1 to 7  6 Excellent Example 6 0.50% 7.00% 1 to 14 7 ExcellentExample 7 0.25% 7.00% 1 to 28 8 Excellent Example 8 1.00% 12.00% 1 to 128 Good Example 9 0.50% 12.00% 1 to 24 9 Good Example 10 0.25% 12.00% 1to 48 10 Good Example 11 1.00% 20.00% 1 to 20 8 Less Good Example 120.50% 20.00% 1 to 40 10 Less Good Example 13 0.25% 20.00% 1 to 80 10Less Good

TABLE 6 1 2 3 4 5 6 7 8 9 10 Char- Very Dark Slightly Gray LightSlightly Off White Very coal/ dark gray dark gray gray white white blackgray gray gray

Mixing may be continued as the silver(II) oxide is introduced, andfurther mixing may ensue, typically for 5-30 minutes. The mixing mayadvantageously produce an intimately dispersed formulation in which thesilver oxide and/or the zinc oxide may be distributed in a homogeneousor substantially homogeneous fashion within the carrier medium. Theformulation may then be poured into storage containers.

Example 15

Using the general procedure provided in Example 14, a water-basedsilver(II) oxide-zinc oxide formulation was prepared. The formulationincluded:

water: 600 grams  (87.1%) bentonite: 25 grams (3.6%) jojoba oil: 15grams (2.2%) zinc oxide: 40 grams (5.8%) silver(II) oxide:  9 grams(1.3%)

Example 16

Using the general procedure provided in Example 14, an emulsion-basedsilver(II) oxide-zinc oxide formulation was prepared. The formulationincluded:

water: 600 grams (63.1%) bentonite:  60 grams (6.3%) jojoba oil: 240grams (25.2%) zinc oxide:  50 grams (5.3%) silver(II) oxide:  0.9 grams(0.1%)

Example 17

A control group of thirty patients was treated at Irvine3Circulation/Vascular Labs (Chieti-Pescara University, Pescara, Italy)using conventional cleaning and compression management methods.

The ulcerations of the patients were diagnosed as resulting from reducedarterial pressure (above-necrosis limits with average skin perfusionpressure >50 mmHg) and diabetic microangiopathy, and were characterizedby localized infection.

Color duplex scanning was used to exclude venous thrombosis, severearterial obstruction, and Doppler techniques were used to evaluate thepresence of tibial pulses, to exclude patients with severe ischemia andnecrosis.

The study of the microcirculation was used to quantify microangiopathyand to follow up subjects after local treatment. Laser Doppler Flowmetry(LDF) was used to assess skin perfusion in association withtranscutaneous oxygen (PO2) measurements.

Example 18

The efficacy of an ointment containing silver tetroxide (AgO) appliedonto the skin surrounding the ulceration was tested at the Irvine3Circulation/Vascular Labs on a treatment group of 29 patients, havingcomparable ulcerations to those of the control group of Example 17.

The ointment, containing approximately 1% AgO was applied around and atthe edge of the ulcerated areas (maximum diameter ranging between 2 cmand 1.1 cm) and on the ulceration, after cleaning, three times daily.The cream was applied after careful washing for 2 minutes in water at40° C. with a sodium hypochlorite based disinfectant (Amuchina®,Angelini Group, Italy) of the ulceration and surrounding area. A neutraladsorbing paper bandage—in contact with the skin—was applied under askin protecting/saving foam layer. An adhesive bandage or an elasticstocking was used to cover the ulcerated area during the observationperiod.

Over the course of the 4-week treatment period, treatment with the AgOointment was found to be more effective than the wound care used in thecontrols. The skin PO2 was increased (28%), and LDF (abnormallyincreased around the ulcerated areas) was decreased (median 29%). Fluxincrease is generally associated with severe microangiopathy. Thevenoarteriolar response of the area was significantly reduced (<30%) atinclusion and improved at the end of the four weeks in the treatmentgroup (+16%).

The ulcer areas were significantly smaller at 4 weeks (the maximumdiameter range was between 0.23 cm and 0; p<0.05) in the AgO-treatedgroup with complete closure in 39% of subjects, vs. 16% in the controls(p<0.05).

Example 19

The efficacy of a silver tetroxide-zinc oxide (AgO—ZnO) ointment on skinulcers was tested at the Irvine3 Circulation/Vascular Labs on atreatment group of 18 patients, versus a control group having 23comparable patients. All patients underwent basic wound care treatmentincluding conventional cleaning and compression management methods.

The ointment, containing 0.99% AgO and 5.0% ZnO in a beeswax and jojobaoil base, was applied around and at the edge of the ulcerated areas(maximum diameter ranging between 2-3 cm and 0.4 cm) and on theulceration, after cleaning, twice daily. A neutral adsorbing paperbandage—in contact with the skin—was applied under a skinprotecting/saving foam layer. An adhesive bandage or an elastic stockingwas used to cover the ulcerated area during the observation period.

Over the course of the 3-week treatment period, treatment with theAgO—ZnO ointment was found to be more effective than the wound care usedin the controls. Moreover, the AgO—ZnO ointment was found to be moreeffective than a similar ointment containing a comparable concentrationof AgO, but no ZnO. The AgO—ZnO ointment was found to improve themicrocirculation and healing rate in both venous ulcerations anddiabetic ulcerations.

Example 20

The efficacy of a silver tetroxide-zinc oxide (AgO—ZnO) ointment onvenous skin ulcers was tested at the Irvine3 Circulation/Vascular Labson a treatment group of 44 patients, versus a control group having 38comparable patients. All patients underwent basic wound care treatmentincluding conventional cleaning and compression management methods.

The ointment, containing 0.87% AgO and 6.8% ZnO in a beeswax and jojobaoil base, was applied, twice daily, around and at the edge of theulcerated areas, after cleaning.

After 4 weeks, the silver tetroxide-zinc oxide treatment proved moreeffective than the control group treatment: skin PO2 was increased 2.1times more than the control group (17.4% to 8.2%) and skin flux (RF) wasimproved 1.6 times with respect to the control group (−38.7% to −24.2%).The total surface area of the ulcer was reduced in the silver treatmentgroup by 88.7%, as opposed to 46.9% in the control group. In addition,in the treatment group, complete closure of the ulceration was observedin 42% of subjects compared to 22% in the control group.

Example 21

The efficacy of the AgO—ZnO ointment of Example 20 on diabeticulcerations was tested at the Irvine3 Circulation/Vascular Labs on atreatment group of 34 patients, versus a control group having 32comparable patients. All patients underwent basic wound care treatmentincluding conventional cleaning and compression management methods.

The ointment was applied, twice daily, around and at the edge of theulcerated areas, after cleaning.

After 4 weeks, the silver tetroxide-zinc oxide treatment proved moreeffective than the control group treatment: skin PO2 was increased 2.6times more than the control group (23.3% to 9.1%) and skin flux (RF) wasimproved 4.3 times with respect to the control group (−26.7% to −6.2%).The total surface area of the diabetic ulcerations was reduced in thesilver treatment group by 89.0%, as opposed to 23.9% in the controlgroup. In addition, in the treatment group, complete closure of theulceration was observed in 39% of subjects compared to 16% in thecontrol group.

Example 22

The anti-microbial efficacy of various formulations was tested andcompared using the following colony counting method:

A freshly opened Muller-Hinton nutrient broth (liquid medium) wasinoculated using a loop full of bacteria (around 100,000-150,000 count).The sample is allowed to rest for 24 hours in the incubator at 37° C.Once the broth is turbid, another full loop is added to several tubes ofnutrient broth, and the broth is allowed to sit for 10 minutes.

A known quantity of each tested formulation is applied onto respectivesterile blank antibiotic discs. After adding one disc to each one of thetubes, the tubes are swirled and allowed to incubate for 24 hours in anincubator at 37° C.

Once the turbidity (bacterial growth) has been achieved after 24 hours,a loop full of each culture is streaked onto a Muller-Hinton agar plateusing the streak plate (“zigzag”) method. The use of a standard loopensures that the same amount of culture is delivered to each plate. Theplates are allowed to mature in an incubator for 24 hours at 37° C.

After 24 hours, the colonies are counted by means of two techniques:

-   -   a manual technique in which a number of 100 is assigned to the        control sample, and based on the density of the colonies in the        other samples, a relative number is assigned based upon visual        evaluation.    -   an automatic colony counter (WU-14025-00 Flash & Grow Colony        Counter, Cole-Palmer®, Vernon Hills, Ill.), which counts the        colonies and is accurate up to 99%.

Examples 23-27

The anti-microbial efficacy of various formulations was tested andcompared using the procedure detailed in Example 22, using Enterococcusfaecalis (ATCC 29212) and water-based formulations containing water,bentonite and jojoba oil. The results are provided below, in Table 7:

TABLE 7 COMPOSI- NUMBER OF SAMPLE/ TION COLONIES EXAMPLE SAMPLE % %COLONY VISUAL NO. TYPE AgO ZnO COUNTER METHOD Nutrient Broth blank — — 00 E. Faecalis control — — 10254 100 23 silver oxide- 1.3  5.8 0 0 zincoxide 24 silver oxide 1.4 — 0 0 25 zinc oxide —  5.9 122 2 26 silveroxide- 1.2 11.0 0 0 zinc oxide 27 silver oxide- 1.1 19.8 0 0 zinc oxide

Examples 28-32

The anti-microbial efficacy of various formulations was tested andcompared using the procedure detailed in Example 22, using Enterococcusfaecalis (ATCC 29212) and oil-based formulations containing beeswax andjojoba oil. The results are provided below, in Table 8:

TABLE 8 COMPOSI- NUMBER OF SAMPLE/ TION COLONIES EXAMPLE SAMPLE % %COLONY VISUAL NO. TYPE AgO ZnO COUNTER METHOD Nutrient Broth blank — — 00 E. Faecalis control — — 10254 100 28 silver oxide- 1.0  7.0 2755 20zinc oxide 29 silver oxide 1.0 — 7327 70 30 zinc oxide —  7.0 14559 12031 silver oxide- 1.0 14.0 N/A* 180 zinc oxide 32 silver oxide-  0.8428.0 N/A* 250 zinc oxide *too thick for quantitative measurement bycolony counter

It is evident from the counting of the colonies, that zinc oxide withoutsilver(II) oxide (Sample 30) is not particularly effective in reducingthe number of colonies, and in fact, a large increase in the number ofcolonies is observed. It is further evident that while silver(II) oxidealone displays some efficacy in reducing the number of colonies (Sample29), that efficacy is greatly enhanced in Sample 28, a formulationcontaining zinc oxide and silver(II) oxide in a 7:1 weight ratio. In theformulations (Samples 31 and 32) containing higher ratios of zinc oxideto silver(II) oxide (about 14:1 to about 33:1), the number of coloniesincreased greatly, to the point that the number could not be measured bythe colony counter.

Example 33

The anti-microbial efficacy of various formulations was tested andcompared using a modified pour plate method. The bacterial population ofa suspension of each test organism was prepared and determined asfollows:

Inoculate the surface of a suitable volume of solid agar medium from arecently revived stock culture of each of the specified microorganisms.

Invert and incubate at 37° C. for 24-48 hours.

Harvest the bacterial cultures, use sterile saline TS or PhosphateBuffer Solution (PBS), wash the surface growth, effect collection in asuitable vessel (e.g., a test tube), and add sufficient sterile salineTS or PBS to obtain a microbial count of about 1×10⁸ colony-formingunits per mL (cfu/ml), which is approximately a McFarland Standard No.1.0 or visible light transmittance of 47-50% at a wavelength of 580 nm.

Measure the suspension concentration by means of a spectrophotometer andadjust the concentration as needed.

Verify the bacterial population of the inoculum:

Add 9 ml of sterile PBS to each of 8 sterile test tubes using sterilepipettes and bulbs. The tubes are kept closed when not in use to preventcontamination.

Withdraw 1 ml (1000 microliters) from the original culture and add to afirst (10⁻¹) tube, mixing so that the bacteria are completely suspendedtherein. Withdraw 1 ml from the first tube and add to a second (10⁻²)tube, mixing as above. Withdraw 1 ml from the second tube and add to athird (10⁻³) tube, mixing as above. Withdraw 1 ml from the third tubeand add to a fourth (10⁻⁴) tube, mixing as above. Withdraw 1 ml from thefourth tube and add to a fifth (10⁻⁵) tube, mixing as above. Withdraw 1ml from the fifth tube and add to a sixth (10⁻⁶) tube, mixing as above.Withdraw 1 ml from the sixth tube and add to a seventh (10⁻⁷) tube,mixing as above. Withdraw 1 ml from the seventh tube and add to aneighth (10⁻⁸) tube, mixing as above.

Prepare plates from the serial dilutions as follows:

Dispense 1 ml from the fourth tube onto the surface of the agar andspread the sample over the entire surface using a sterile cell spreader(L-shaped glass rod). To sterilize the cell spreader, dip in ethanol inplate and flame only to burn off the alcohol. Repeat this procedure fortwo additional plates, by dispensing 1 ml from each of the sixth tubeand the eighth tube into respective plates. Allow plates to dry for 5minutes before inverting for incubation for 24-48 hours at 37° C.

Record the colony counts and calculations as follows:

Identify two plates of the same dilution, having between 30 and 300colonies. Count the number of bacterial colonies (regardless of size) onthat plate, record the results, and calculate the average count.Calculate the approximate number of organisms in the original cultureusing the average counts in the selected dilution plates.

Pour 20 ml Tryptic Soy Agar (TSA) into each Petri dish (100×15 mm). In asuitable flask or bottle, weigh the desired amount of the dehydratedagar and achieve the concentration recommended by the manufacturer usingdeionized water. Place on top of a hot plate having a stirrer and bringthe bottle to a boil. After boiling, transfer the bottle to a water bathpreviously set at 45° C. Monitor the temperature of the agar until thetemperature stabilizes at 45° C.

Aseptically weigh out 10 g of the test product in a sterile sample cup.When formulations containing significantly different concentrations ofAgO are being compared, the weight of the test product may be adjustedto keep the total amount of AgO constant for all samples. Add inoculum(typically about 0.1 ml) to the test product in the sample cup such thatthe final concentration of microorganisms in the test product isapproximately 1×10⁶ cfu per gram. Using a sterile glass rod, mixthoroughly to obtain a homogeneous sample.

Aseptically collect 0.1 g of the inoculated test product into thesterile Petri dish at 0, 10, and 30 minutes and at 1, 2, 3, 4, 18 and 24hours. Add 2 ml of Mueller-Hinton Broth to neutralize the effect of theproduct, mix well.

Pour 20 ml of TSA (45° C.) into the inoculated Petri dish. Cover and mixthoroughly by gentle tilting and swirling the dish on a flat, levelsurface. Place at room temperature on a flat surface undisturbed forabout 10 minutes to allow the agar to completely gel. Invert andincubate at 37° C. for 24-48 hours.

After 24 hours, the colonies are counted by means of a manual techniquein which a number of 100 is assigned to the control sample, and based onthe density of the colonies in the other samples, a relative number isassigned based upon visual evaluation.

Examples 34-38

The modified pour plate method of Example 33 was used to evaluate theefficacy of various formulations on test organisms such as Enterococcusfaecalis and water-based formulations containing water, bentonite andjojoba oil. The results are provided below, in Table 9:

TABLE 9 COMPOSI- NO. OF SAMPLE/ TION COLONIES EXAMPLE SAMPLE % % VISUALNO. TYPE AgO ZnO METHOD E. Faecalis control — — 100 34 silver(II) oxide-1.3  5.8 10 zinc oxide 35 silver(II) oxide 1.4 — 15 36 zinc oxide —  5.980 37 silver(II) oxide- 1.2 11.0 10 zinc oxide 38 silver(II) oxide- 1.119.8 10 zinc oxide

It is evident from the manual counting of the colonies, that zinc oxidewithout silver(II) oxide (Sample 36) is not particularly effective inreducing the number of colonies. It is further evident that whilesilver(II) oxide alone displays efficacy in reducing the number ofcolonies (Sample 35), that efficacy is greatly enhanced in Sample 34, aformulation containing zinc oxide and silver(II) oxide in or up to a4.5:1 weight ratio. The formulations containing higher ratios of zincoxide to silver(II) oxide (about 9:1 to 18:1), also exhibit enhancedefficacy in reducing the number of colonies.

Examples 39-43

The modified pour plate method of Example 33 was used to evaluate theefficacy of various formulations on test organisms such as Enterococcusfaecalis and oil-based formulations. The results are provided below, inTable 10:

TABLE 10 COMPOSI- NO. OF SAMPLE/ TION COLONIES EXAMPLE SAMPLE % % VISUALNO. TYPE AgO ZnO METHOD E. Faecalis control — — 100 39 silver(II) oxide-1.0  7.0 15 zinc oxide 40 silver(II) oxide 1.0 — 80 41 zinc oxide —  7.0130 42 silver(II) oxide- 1.0 14.0 160 zinc oxide 43 silver(II) oxide- 0.84 28.0 180 zinc oxide

FIG. 5 provides top view photographs of Petri dishes containingoil-based formulations and identically grown cultures according to amodified pour plate method, wherein: FIG. 5A shows a cultured Petri dishafter being exposed to a formulation containing 1.0% AgO and 7.0% ZnO(Sample 39); FIG. 5B shows a cultured Petri dish after being exposed toa formulation containing 1.0% AgO and no ZnO (Sample 40); FIG. 5C showsa cultured Petri dish after being exposed to a formulation containing7.0% ZnO and no AgO (Sample 41); FIG. 5D shows a cultured Petri dishafter being exposed to a formulation containing 1.0% AgO and 14.0% ZnO(Sample 42); and FIG. 5E shows a cultured Petri dish after being exposedto a formulation containing 0.84% AgO and 28.0% ZnO (Sample 43).

It is evident from the photographs, and from the manual counting of thecolonies, that zinc oxide is not effective in reducing the number ofcolonies. It is further evident that while silver(II) oxide alonedisplays efficacy in reducing the number of colonies, that efficacy isgreatly enhanced in Sample 39, a formulation containing zinc oxide andsilver(II) oxide in or up to a 7:1 weight ratio. However, withformulations containing high ratios of zinc oxide to silver(II) oxide(14:1 or higher, as in Samples 42 and 43), the formulation shows poorefficacy in reducing the number of colonies.

These results have some similarities to the results obtained usingwater-based formulations, but also exhibit some differences, mostnotably relating to the performance of formulations having high ratiosof zinc oxide to silver(II) oxide. Without wishing to be bound bytheory, I believe that in water-based formulations, the availablesilver(II) oxide concentrations are appreciably higher, such that thehigh concentration of zinc oxide may not impede, or largely may notimpede, the anti-microbial action of the silver(II) oxide. In oil-basedformulations, by sharp contrast, the zinc oxide, at high concentrations,may cover or impede the contact of the silver(II) oxide with themicroorganisms, and thus compromises the anti-microbial efficacy. At lowconcentrations of zinc oxide, however, the zinc oxide may act as a soliddispersant with respect to the silver(II) oxide, thereby greatlyincreasing the available specific surface area thereof, but withoutsubstantial covering of the silver(II) oxide particles.

Example 44

The anti-microbial efficacy of various formulations was tested andcompared using a Kirby-Bauer type test, as follows:

Ready-made Muller-Hilton agar was streaked with the bacterial inoculumusing a sterile applicator. The sample was allowed to sit for 5 minutesto ensure that the bacteria adhere to the surface of the agar.Subsequently, an antibiotic sterile blank disc was pressed against aknown quantity of the formulation being tested. While the amount appliedto each disc was not measured, care was taken to obtain a consistentamount of material on each disc. Multiple duplicate discs were used toverify the data. The disc was pressed against the surface of the agar,making sure not to damage the disc or the agar. Each agar plate was theninverted and allowed to sit in the incubator at 37° C. for 24 hours. Theplates were subsequently removed from the incubator, and the zone ofinhibition was measured using a ruler.

Examples 45-46

The anti-microbial efficacy of various oil-based and water-basedformulations was tested and compared using the procedure detailed inExample 44, using various individual strains of bacteria such asEnterococcus faecalis and Staphylococcus aureus (ATCC No. 25923).

Two oil-based formulations were tested several times againstEnterococcus faecalis: Sample 45, a two-month old sample containing 1.0%AgO and no zinc oxide, disposed in a beeswax and jojoba oil base, andSample 46, a two-month old sample containing 0.87% AgO and 6.8% ZnO,also disposed in a beeswax and jojoba oil base.

In the case of Sample 45, the zone of inhibition averaged approximately4 mm; in the case of Sample 46, the zone of inhibition averagedapproximately 18 mm. The relatively wide zone of inhibition achieved bySample 46 indicates improved anti-microbial efficacy with respect toSample 45, despite a lower total content of AgO.

It would appear that the improved anti-microbial efficacy in theseoil-based formulations is attributable to the presence of zinc oxide inSample 41, and more particularly, to the presence of zinc oxide in aweight ratio of less than 14:1, less than 12:1, and less than 10:1.Without wishing to be bound by theory, I believe that, as statedhereinabove, the zinc oxide may act as a solid dispersant with respectto the silver(II) oxide, thereby greatly increasing the availablespecific surface area thereof, but—within or below these weightratios—without substantial covering of the silver(II) oxide particles.

The medical device of the present invention may also contain both asilver oxide compound and a whitening agent, preferably in a carriermedium that may be a water-based cream or lotion, or an ointment thatmay include a wax and/or an oil. The formulation may include anemulsion, or be substantially emulsion-based.

FIG. 6 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for formulations containing AgO (1%)and Ag₂O (1%), in a carrier base described in Example 1 hereinbelow.After preparing the formulations, the whiteness was measured byreflectance using a LabScan XE spectrophotometer instrument (HunterLab,VA). Initially, the AgO formulation was a relatively dark gray, and theinitial value of whiteness was 2.72 reflective units. The Ag₂Oformulation also had a dark gray color, albeit somewhat lighter than theAgO formulation, and exhibited an initial value of whiteness of 3.72reflective units.

The formulations were then subjected to ultraviolet light for severaldays, and the whiteness of each of the formulations was monitored overtime. We found that the measured reflectance or lightness of the AgOformulation decreased monotonically over time, as the formulation tookon a progressively darker hue of gray. The reflectance decreased to 1.74reflective units after 3 days, and further decreased to 1.02 reflectiveunits after 6 days. Similarly, the measured reflectance or lightness ofthe Ag₂O formulation decreased monotonically over time, as the grayformulation became progressively darker. The reflectance decreased to3.35 reflective units after 1 day, 2.65 reflective units after 3 days,and further decreased to about 1.9 reflective units after 6 days.

FIG. 6A is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for three formulations containingAgO (1%): the first formulation is the formulation associated with FIG.1, containing AgO in the “standard base” (described in detail in Example1 hereinbelow); the second formulation contained an oxidizedpolyethylene homopolymer (Honeywell A-C® 629), jojoba oil, and xanthumgum (“Base 1”); and the third formulation contained beeswax, coconut oiland xanthum gum (“Base 2”). The three formulations exhibit a similarmonotonous decrease in lightness over the six-day exposure period.

Without wishing to be limited by theory, we believe that silver oxide(including both silver(II) oxide and silver(I) oxide), being a reactivematerial, interacts with at least one other material within theformulation, causing discoloration over time. This effect may beaccelerated or augmented by exposure to sunlight. In sunlight, thediscoloration may be apparent even within minutes.

We have found that this effect may actually be an acceleration of aprocess that occurs, albeit much more slowly, when the silver oxidebased formulation is packaged in a container. Thus, the discolorationphenomenon may be significant because:

-   -   topical formulations, applied to the skin, are commonly exposed        to sunlight; and    -   the shelf life of silver oxide based formulations may be        severely limited by the discoloration process occurring within        the container.

By adding various whiteners during the preparation of the formulations,we found that the appearance of the formulations became significantlylighter. In the case of zinc oxide, the measured whiteness value of thesilver(II) oxide formulation (1% AgO, 7% ZnO) increased by almost 3reflectance units, to about 5.43, and the measured whiteness value ofthe silver(I) oxide formulation (1% Ag₂O, 7% ZnO) increased by slightlymore than 3 reflectance units, to about 6.87. In the case of titaniumdioxide, the measured whiteness value of the formulation (1% AgO, 7%TiO₂) nearly doubled to about 5.33. Such light-colored formulations(cream, ointment, etc.) are much more aesthetically pleasing to users,and may pose less of a problem regarding staining of skin and clothing.

These formulations were then subjected to ultraviolet light for severaldays, in a procedure substantially identical to that used on theformulations described hereinabove, and the whiteness of each of theformulations was monitored over time. FIG. 7 is a graph plottingformulation lightness, as a function of the exposure time to ultravioletlight, for the AgO formulation of FIG. 6, versus similar formulationscontaining AgO along with the inorganic whiteners ZnO and TiO₂,respectively. It may have been expected that the whiteners would coverup a portion of the AgO, producing a lighter formulation in which theAgO is also less exposed to the ultraviolet light, such that duringexposure to ultraviolet light, the decrease in whiteness might be muchmore moderate.

Surprisingly, we found that with both ZnO and TiO₂, the decrease inwhiteness, as a function of UV exposure time, may actually be morepronounced than the corresponding decrease in whiteness of the identicalformulation, without the additional whitener. In the case of the AgO/ZnOformulation, the whiteness value decreased by 2 reflective units within3 days, and by 2.7 reflective units within 6 days.

Similar results were obtained with Ag2O: after 3 days, the whitenessvalue of an AgO/ZnO (1%, 7%) formulation decreased by about 1.9reflective units; the whiteness value of an AgO/ZnO/TiO₂ (1%, 3.5%,3.5%) formulation decreased by about 3.8 reflective units.

Thus, while the use of such whiteners greatly improved the initialformulation color, the use of these whiteners raised additional issues.Both silver(I) and silver(II) oxides may interact with the zinc oxideand titanium dioxide, or with the carrier base in the presence of zincoxide and/or titanium dioxide, causing significant discoloration withina day or days. This effect may be accelerated or augmented by exposureto direct sunlight, in which the discoloration may be effected withinminutes.

Many of the tests on AgO-based formulations have been repeated forAg₂O-based formulations, which typically provide qualitatively similarresults.

FIG. 8 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for the formulations of FIG. 7,versus similar formulations containing AgO along with the inorganicsubstances bentonite, CaCO₃, Ca(OH)₂ and MgSO₄, respectively. All of themixed formulations contained 1% AgO and 7% of the additional inorganicmaterial, to provide a firm basis of comparison.

Immediately after preparation, all of the mixed formulations whitenerswere significantly lighter than the AgO standard formulation. TheAgO/bentonite formulation exhibited a reflectance just over 4 reflectiveunits, a 48% increase with respect to the AgO standard formulation. TheAgO/Ca(OH)₂ and AgO/MgSO₄ formulations both exhibited a reflectance ofalmost 5 reflective units (4.9 and 4.97, respectively), corresponding tomore than an 80% increase with respect to the AgO standard formulation.In the case of calcium carbonate, the measured whiteness value of theformulation (1% AgO, 7% CaCO₃) more than doubled to about 5.67.

The formulations were then subjected to ultraviolet light for severaldays, as described hereinabove, and the whiteness of each of theformulations was monitored over time. All of the formulations exhibiteddecreasing whiteness, as a function of UV exposure time. With theexception of the AgO/TiO₂ formulation, all of the formulations maintaina substantially higher reflectance after 1 day, after 3 days, and after6 days. Moreover, we observe that the decreasing whiteness is lesspronounced in some of the formulations.

FIG. 8A presents a graph plotting normalized formulation whiteness(W_(N)) as a function of the exposure time to ultraviolet light, for theformulations of FIG. 8. The normalization is based on the initialformulation whiteness (normalized reflectance or whiteness equals 1 att=0). It is readily observed that the performance of the AgO/TiO₂formulation is appreciably worse than that of the standard AgOformulation, with the normalized whiteness dropping below 0.3 after 3days of UV exposure. The performance of the AgO/ZnO and AgO/MgSO₄formulations is fairly similar to that of the standard AgO formulation,with the normalized whiteness dropping to about 0.63 and 0.65,respectively, after 3 days of UV exposure.

The other formulations, containing AgO along with bentonite, CaCO₃, andCa(OH)₂, respectively, all exhibit a normalized formulation whitenessexceeding 0.7 after 3 days of UV exposure. The 1% AgO, 7% CaCO₃formulation exhibited a normalized formulation whiteness approaching0.7, even after 6 days of UV exposure.

FIG. 8B presents a graph plotting the absolute decrease in formulationreflectance (in RU) as a function of the exposure time to ultravioletlight, for the formulations of FIG. 3. While all of the formulationsexhibited decreasing whiteness, as a function of UV exposure time, theabsolute decrease in reflectance for the AgO/ZnO and the AgO/TiO₂formulations was over 2-4 times the absolute decrease in reflectance forthe AgO formulation after 1 day of UV exposure, and about 2-4 times theabsolute decrease in reflectance for the AgO formulation after 3 days ofUV exposure. With the exception of the AgO/TiO₂ formulation, all of theformulations maintain a substantially higher reflectance after 1 day,after 3 days, and after 6 days.

By sharp contrast, the absolute decrease in reflectance for theformulations containing AgO along with bentonite, CaCO₃, MgSO₄, andCa(OH)₂, was reduced with respect to the absolute decrease inreflectance for the AgO formulation after both 1 day and 3 days of UVexposure.

FIG. 9 is a comparison graph plotting formulation whiteness, as afunction of the exposure time to ultraviolet light, for the formulationsof FIG. 7, versus similar formulations containing AgO along with theinorganic substances Mg(OH)₂, MgCO₃, and MgO, respectively. All of themixed formulations contained 1% AgO and 7% of the additional inorganicmaterial.

Immediately after preparation, all of the mixed formulations whitenerswere significantly lighter than the AgO standard formulation. TheAgO/Mg(OH)₂ formulation exhibited 5.33 reflective units, a 96% increasewith respect to the AgO standard formulation. The AgO/MgO and AgO/MgCO₃formulations exhibited almost 5.5 and 6.01 reflective units,respectively, corresponding to more than a 100% or 120% increase withrespect to the AgO standard formulation.

The formulations were then subjected to ultraviolet light for severaldays, as described hereinabove, and the whiteness of each of theformulations was monitored over time. Although these formulationsexhibited decreasing whiteness, as a function of UV exposure time, thedecreasing whiteness was surprisingly moderate.

FIG. 9A presents a comparison graph plotting normalized formulationwhiteness (W_(N)) as a function of the exposure time to ultravioletlight, for the formulations of FIG. 9. The AgO/Mg(OH)₂, AgO/MgO andAgO/MgCO₃ formulations, all exhibit a normalized formulation whitenessapproaching or exceeding 0.9 after 3 days of UV exposure, andapproaching or exceeding 0.8 after 6 days of UV exposure. The 1% AgO, 7%MgO formulation exhibited a normalized formulation whiteness exceeding0.9, even after 6 days of UV exposure.

FIG. 9B presents a graph plotting the absolute decrease in formulationreflectance (in RU) as a function of the exposure time to ultravioletlight, for the formulations of FIG. 9. While all of the formulationsexhibited decreasing whiteness, as a function of UV exposure time, theabsolute decrease in reflectance for the AgO/Mg(OH)₂, AgO/MgO andAgO/MgCO₃ formulations was significantly less than that of the AgOformulation after 1 day of UV exposure, after 3 days of UV exposure, andafter 6 days of UV exposure.

Over the course of clinical trials, we have found that treating woundswith an AgO/ZnO formulation may be considerably more efficacious thanconventional treatments used in the controls. Moreover, the AgO/ZnOformulation exhibited a higher efficacy than a similar formulationcontaining a comparable concentration of AgO, but no ZnO. In addition,the AgO/ZnO formulation was found to improve the microcirculation andhealing rate in both venous ulcerations and diabetic ulcerations.

The darkening of the AgO/ZnO formulation over time, and during exposureto UV light, may be a disadvantage in many applications. As best seen inFIG. 7, the darkening of AgO/ZnO formulations may be rapid andappreciable. After only one day of UV exposure, the “white” AgO/ZnOformulation has become nearly as dark as the identical formulation,without ZnO; after three days of UV exposure, the AgO/ZnO formulationlooks extremely similar to that formulation, and may actually be evendarker. Thus, while the ZnO contributes to the formulation efficacy, thecontribution to the whiteness may be surprisingly modest. In addition,the dark appearance of the formulation, developed over time, may reducepatient compliance.

We have found that the appearance of formulations containing AgO and ZnOmay be greatly enhanced by the addition of at least one stabilizationagent adapted to at least partially inhibit a darkening of theformulation when exposed to ultraviolet light. The stabilization agentmay advantageously act as a whitener as well.

FIG. 10 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, showing the whiteness stabilizationperformance of various inorganic substances in formulations containingAgO and ZnO. As described hereinabove, the decrease in whiteness of theAgO/ZnO control or base formulation (1% AgO/7% ZnO), as a function of UVexposure time, is more pronounced than the corresponding decrease inwhiteness of the identical AgO formulation, without the zinc oxide. Whenhalf of the zinc oxide is replaced with titanium dioxide, the initialwhiteness is improved, but after three days of UV exposure, thewhiteness exhibited by the AgO/ZnO/TiO₂ formulation (1% AgO/3.5%ZnO/3.5% TiO₂) is significantly lower than that of the base formulation.

By sharp contrast, when half of the zinc oxide is replaced withmagnesium oxide, the initial whiteness is substantially maintained, butover the course of several days of UV exposure, the whiteness exhibitedby the AgO/ZnO/MgO formulation (1% AgO/3.5% ZnO/3.5% MgO) issignificantly higher than that of the base formulation. Surprisingly,the whiteness stays fairly constant over the first three days of UVexposure, and—perhaps even more surprisingly, the whiteness exhibitedappears to be very similar to the whiteness (plotted in FIG. 5, as areference line) of an AgO/MgO formulation containing 1% AgO, 7% MgO, andhaving no ZnO.

Similarly, when half of the zinc oxide is replaced with calciumcarbonate (CaCO₃), the initial whiteness is substantially maintained.Over the course of several days of UV exposure, the whiteness exhibitedby the AgO/ZnO/CaCO₃ formulation (1% AgO/3.5% ZnO/3.5% CaCO₃) issomewhat higher than that of the base formulation. Surprisingly, throughthe third day of UV exposure, the whiteness exhibited appears to besimilar to the whiteness (plotted in the Figure, as a reference line) ofan AgO/CaCO₃ formulation containing 1% AgO, 7% CaCO₃, and having no ZnO.

FIG. 11 is a graph plotting the whiteness behavior of various AgO basedformulations and the whiteness behavior of various Ag₂O basedformulations, as a function of the exposure time to ultraviolet light.All of the mixed formulations contained 1% AgO or Ag₂O, and 7% of theadditional inorganic material—MgO or CaCO₃, respectively.

The formulations were subjected to ultraviolet light for several days,as described hereinabove, and the whiteness of each of the formulationswas monitored over time. Although the mixed formulations exhibiteddecreasing whiteness as a function of UV exposure time, the decreasingwhiteness was surprisingly moderate for both AgO-based and Ag₂O-basedmixed formulations.

Moreover, we have found with these exemplary mixed formulations, as wellas with other mixed formulations, that the behavior of the Ag₂O-basedformulations and the Ag₂O-based formulations, with respect to UV lightexposure, is strikingly similar. By way of example, the measuredwhiteness for AgO/CaCO₃, and Ag₂O/CaCO₃, is virtually identical forexposure times of 1 day, 3 days and 6 days.

Similarly, the measured whiteness values for the AgO/MgO and Ag₂O/MgOformulations, respectively, are within 5% of each other initially, andremain within about 7% of each other for exposure times of 1 day, 3 daysand 6 days.

FIG. 11A presents a graph plotting normalized formulation reflectance orwhiteness (W_(N)) as a function of the exposure time to ultravioletlight, for six silver oxide formulations (1% by weight) having differentcarrier bases. Two of the formulations contained solely (i.e., sanswhiteners or stabilization agents) 1% AgO in Base 1 or in Base 2,respectively; two of the formulations contained 1% AgO and 7% CaCO₃, inthe standard base or in Base 2, respectively; and two of theformulations contained 1% AgO and 7% MgO in the standard base or in Base1, respectively.

Despite the significant differences in the chemical and physicalproperties of the carrier bases, we observe that the behavior of eachtype of formulation appears to be largely insensitive to the compositionof the carrier base.

FIG. 12 provides a graph plotting formulation whiteness, as a functionof the exposure time to ultraviolet light; the graph demonstrates thewhiteness stabilization performance of various inorganic substances informulations containing Ag₂O and ZnO. The decrease in whiteness of theAg₂O/ZnO control or base formulation (1% Ag₂O/7% ZnO), as a function ofUV exposure time, may be more pronounced than the corresponding decreasein whiteness of the identical Ag₂O formulation, without the zinc oxide(not shown). When half of the zinc oxide is replaced with titaniumdioxide, the results are still very poor: after only one day of UVexposure, the whiteness value exhibited by the Ag₂O/ZnO/TiO₂ formulation(1% Ag₂O/3.5% ZnO/3.5% TiO₂) is more than 40% lower than the initialwhiteness.

By sharp contrast, when half of the zinc oxide is replaced withmagnesium oxide, the initial whiteness value is somewhat lower, butafter three days of UV exposure, the whiteness value exhibited by theAg₂O/ZnO/MgO formulation (1% Ag₂O/3.5% ZnO/3.5% MgO) is significantlyhigher than that of the Ag₂O—ZnO formulation (1% Ag₂O/7% ZnO).Surprisingly, the whiteness value stays fairly constant over the firstthree days of UV exposure. The whiteness value exhibited appears to behigher than the whiteness value (plotted in FIG. 12 as a reference line)of an Ag₂O/MgO formulation containing 1% Ag₂O, 7% MgO, and having noZnO.

The Ag₂O/ZnO/CaCO₃ formulation (1% AgO/3.5% ZnO/3.5% CaCO₃) exhibitspoor whiteness values when compared with both 1% Ag₂O/7% ZnO and with 1%Ag₂O/7% CaCO₃.

Typically, the inventive formulations contain up to 5% silver oxide orup to 3% silver oxide, by weight. More typically, the formulationscontain 0.01% to 3% silver oxide. The ratio of the whitener (withoutzinc oxide) and the stabilization agent to the silver oxide, within theformulation, is typically at least 0.2:1, at least 0.3:1, at least0.5:1, at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least5:1, at least 7:1, or at least 10:1, by weight.

In preparing the various formulations of the present invention, we havediscovered that within a specified range of weight ratios and/orcompositions, the silver oxide based formulation is highly spreadable,despite the presence of the chalky whiteners and/or stabilizationagents. We have found that formulations containing more than 20-25%, byweight, of the whiteners and/or stabilization agents, may display poorspreadability, and may generally be less efficacious from ananti-microbial standpoint.

Thus, the inventive formulations may contain up to 20% by weight, of atleast one whitener and/or stabilization agent, more typically, up to 17%by weight, and more typically, up to 15% by weight. The formulations maytypically contain at least 0.2%, at least 0.5%, at least 1%, at least2%, at least 3%, or at least 5%, by weight, of the whitener and/orstabilization agent. Most formulations contain between 2% and 15%,between 2.5% and 12%, or between 3% and 10%, by weight, of the whitenerand/or stabilization agent.

When both a whitener (e.g., zinc oxide) and a stabilization agent (e.g.,Mg(OH)₂ or MgO) are used, the formulations may typically contain atleast 0.2%, at least 0.5%, at least 0.8%, at least 1%, at least 2%, atleast 3%, or at least 5%, by weight, of the whitener, and moretypically, between 0.8% to 10%, between 0.8% to 8%, or between 0.8% to6%, by weight. The formulations may typically contain at least 0.2%, atleast 0.5%, at least 0.8%, at least 1%, at least 2%, at least 3%, or atleast 5%, by weight, of the stabilization agent, and more typically,between 0.8% to 8%, between 0.8% to 6%, or between 0.8% to 4%.

The ratio of stabilization agent to whitener may vary greatly, but istypically at least 0.1:1, at least 0.25:1, at least 0.5:1, at least 1:1,at least 2:1, at least 3:1, or at least 5:1, by weight. Typically, theratio of stabilization agent to whitener may be up to 15:1, up to 12:1,up to 10:1, or up to 8:1, by weight.

Example 47

The exemplary “standard base” silver oxide formulations providedhereinabove were prepared according to the following general procedure:jojoba oil was heated to 80° C. Beeswax was introduced, and the materialwas mixed thoroughly during cooling to about 55° C. Palmarosa oil wasadded, followed by at least one of a silver (II) oxide (AgO) and silver(I) oxide (Ag₂O). Where appropriate, a solid (acting as a whitenerand/or stabilization agent) such as an inorganic powder was introducedalong with the silver oxide, although practical considerations maysuggest that the addition be made prior to the introduction of thesilver oxide, or sometime thereafter.

Mixing may be maintained throughout, and during cooling of the mixtureto 35° C.-40° C.

Alternatively or additionally, various base components that are known tothose skilled in the art may be used, including petrolatum, polyethylenepolymers (such as: oxidized polyethylene homopolymer (Honeywell A-C®629)), mineral oil, coconut oil, xanthum gum.

In the exemplary formulations described hereinabove, the weight ratio ofthe jojoba oil to beeswax was about 5.5 to 1. The palmarosa oil contentwas about 0.04% of the jojoba oil content. The total content of thebeeswax, jojoba oil, silver oxide, and one or more whiteners andstabilization agents, within the formulations, typically exceeded 99%.

Example 48

An exemplary general procedure for producing the inventive silver oxidebased cream is as follows: a base material such as liquid wax ester(e.g., jojoba oil) is heated, preferably to around 80° C. Alternativelyor additionally, various base components may be used, base componentsthat will be known to those skilled in the art of topical formulationproduction, such as, but not limited to, petrolatum, polyethylenepolymers (such as an oxidized polyethylene homopolymer (Honeywell A-C®629)), mineral oils, coconut oil, and xanthum gum.

A thick base material (e.g., a wax such as beeswax, polyethylenepolymers, or hydrogenated jojoba oil or the like) may be melted into theliquid wax ester or base material. The mixture may be mixed thoroughlyas it is cooled, typically below about 60° C. An essential oil such aspalmarosa oil may be added. Mixing may be continued as at least one of awhitener and a stabilization agent (both in the form of solid powders)is introduced. At least one silver oxide such as a silver (II) oxide ora silver (I) oxide is also introduced, before, after, or concurrentlywith the whitener and stabilization agent, and the mixing may becontinued during cooling of the mixture to below about 40° C. The mixingmay advantageously produce an intimately dispersed formulation in whichthe silver oxide and the whitener and/or stabilization agent may bedistributed in a homogeneous or substantially homogeneous fashion withinthe carrier medium.

Example 48A

Water-based and emulsion-based formulations according to the presentinvention may be prepared according to the following exemplaryprocedure: to a container containing water or an aqueous solution may beadded a viscosity-building agent (e.g., a smectite such as a bentoniteor montmorillonite powder such as Gelwhite H, produced by Southern ClayProducts, Inc., Gonzales, Tex.). Other viscosity-building clays,particularly clays in which the silicate layers are disposed in asandwiched structure, may also be used. Other viscosity-building agentsand thickeners may be used, e.g., carbomers. Preferably, such selectedmaterials may exhibit good resistance to oxidation or chemical attack bythe silver oxide or oxides.

The mixture is mixed or homogenized, typically for 0.5 to 2 hours.Silver(II) oxide and/or silver(I) oxide may be introduced at this stageof the processing. The whitener(s) and/or stabilization agent(s) may beintroduced to the mixture, typically along with the silver oxide, orsometime therebefore or thereafter. The oil and/or liquid wax ester(e.g., jojoba oil) may be introduced to the mixture during the mixing(e.g., blending or homogenizing).

Examples 49-54

Six formulations were prepared according to the general procedureprovided above. The control formulation contained 1% AgO, 7% ZnO, and noadditional whitener or stabilizing agent. The other five formulationscontained various quantities of MgO, such that the total amount of zincoxide and magnesium oxide equaled 7%. The composition of eachformulation, along with the weight ratios of magnesium oxide to zincoxide and magnesium oxide to silver oxide, are provided below in TABLE11:

TABLE 11 COMPOSITION (Wt. %) WEIGHT RATIOS Formulation AgO ZnO MgOMgO:ZnO MgO:AgO A (Example 49) 1 7 0 0.00 0.00 B (Example 50) 1 6.3 0.70.11 0.70 C (Example 51) 1 4.9 2.1 0.43 2.10 D (Example 52) 1 3.5 3.51.00 3.50 E (Example 53) 1 2.1 4.9 2.33 4.90 F (Example 54) 1 0.7 6.39.00 6.30

About 1 gram of each of Formulations B-F was smeared on a piece of 100%white cotton cloth, which was then exposed to white UV light for aboutone month. Periodically, the cloth was examined for change in color, andphotographed.

FIG. 13A provides a photograph of Formulations B-F (ordered from left toright) after 3 days of constant exposure to UV light. It is clearlyobserved that staining or darkness is inversely related to the amount ofMgO. Formulation B, though having a rather dark appearance, is actuallylighter than Formulation A (not shown). The stain from Formulation C isdark solely near the perimeter; the stain associated with Formulation Dis dark solely near a portion of the perimeter; the stains associatedwith Formulations D and E, respectively, are light throughout. Thus, asthe content of MgO within the formulation becomes correspondinglyhigher, the staining appears to be lighter and less pronounced. It isfurther evident from the stains and from the data in TABLE 11 thatreduced staining (or formulation lightness) may be proportionallyrelated to, or may positively depend on, at least one of the weightratio of MgO:ZnO and MgO:AgO.

These observations may be further supported by the photographs of thestains provided in FIGS. 13A and 13B, taken 10 days and 21 days,respectively into the experiment. As before, the cloth underwentconstant exposure to UV light. After 10 days, Formulation D is lighterthan Formulation B after 3 days. Even after 21 days, Formulation F islighter than Formulation B after 3 days.

Perhaps more significantly, all of the formulations containing MgOappear to be lighter than corresponding Formulation A, which contains noMgO.

Example 55

Formulation reflectance, lightness, or whiteness was evaluated asfollows: approximately 1 gram of a particular sample (typically anointment or cream) was spread on a 5 cm by 5 cm area of white cottoncloth and distributed evenly, typically using a metal spatula.

A LabScan XE spectrophotometer instrument (HunterLab, VA) was used toevaluate the reflectance of each sample. The working principle of theinstrument pertains to the property of light reflection. The clothsample is stored in a completely dark container. To measure thereflectance, the instrument exposes the sample to a controlled,repeatable pulse of light. The lightness of the sample is generallycorrelated with the reflectance: higher values correspond to lightersamples.

The spectrophotometer has a wavelength range of 375 nm to 750 nm and anoptical resolution of 10 nm. The spectrophotometer measures reflectedcolor using 0°/45° geometry.

Example 56

Formulation reflectance was evaluated as a function of the exposure timeto ultraviolet light, as follows: the LabScan XE spectrophotometerdescribed in Example 9 was used. Each sample was continuously exposed toultraviolet light produced by the illumination source. The continuous UVexposure is through a 254 nm, 6 W UV bulb distributed by Cole-Parmer®.The distance between the UV source and the specimen or formulation was18 inches (˜45.7 cm).

Sample preparation was substantially the same as that described inExample 55. After an initial measurement (“day 0”), additionalmeasurements were made over the course of the exposure to ultravioletlight, typically on days 1, 3 and 6.

Examples 57-61

Five formulations were prepared according to the general procedureprovided above. All the formulations contained 1% AgO, and weredistinguished by their varying concentrations of MgO. Example 49 isprovided for comparative purposes. The composition of each formulation,along with the weight ratios of magnesium oxide to silver oxide, areprovided below in TABLE 12:

TABLE 12 COMPOSITION (Wt. %) WEIGHT RATIO Formulation AgO ZnO MgOMgO:AgO G (Example 49) 1 7 0 0.0 H (Example 57) 1 0 0 0.0 I (Example 58)1 0 3.5 3.5 J (Example 59) 1 0 7.0 7.0 K (Example 60) 1 0 14 14 L(Example 61) 1 0 28 28

FIG. 14 is a graph plotting formulation whiteness, as a function of theexposure time to ultraviolet light, for formulations containing AgO andvarying concentrations of MgO, versus similar formulations containingsolely AgO (Example 11), and AgO and ZnO (Example 49). FIG. 14A is amagnified, partial view of the graph of FIG. 14, showing exposure timesof up to 3 days. FIG. 14B provides a graph plotting normalizedformulation whiteness (W_(N)) as a function of the exposure time toultraviolet light, for the formulations of FIG. 14A.

We observe that in all of the formulations containing MgO, the MgObehaved as a whitener and as a stabilizing agent. The initial whitenessvalues of the MgO-containing formulations were about 5 to 5.5reflectance units. After one day of exposure to ultraviolet light, thewhiteness values of the MgO-containing formulations dropped slightly,remaining close to or about 5 to 5.5 reflectance units. After three daysof exposure to ultraviolet light, the whiteness values of theMgO-containing formulations dropped slightly, to about 4.6 to 5.3reflectance units. After thirteen days of exposure to ultraviolet light,the whiteness values of the MgO-containing formulations droppedslightly, to about 4.0 to 4.6 reflectance units.

In FIG. 14B, we observe that after three days of exposure to ultravioletlight, the MgO-based formulations retained between 92% and 98% of theirinitial whiteness values. Formulation L, containing a 28:1 ratio of MgOto AgO, retained approximately 98% of its initial whiteness value;Formulation K, containing a 14:1 ratio of MgO to AgO, retainedapproximately 97% of its initial whiteness value; Formulation J,containing a 7:1 ratio of MgO to AgO, retained approximately 96% of itsinitial whiteness value; and Formulation I, containing a 3.5:1 ratio ofMgO to AgO, retained approximately 92% of its initial whiteness value.Another formulation, containing a 1:1 ratio of MgO to AgO, retainedalmost 80% of its initial whiteness value, after three days of exposureto ultraviolet light. Moreover, even a formulation containing a 0.5:1ratio of MgO to AgO acted as a stabilization agent over the course of atleast one day of exposure to ultraviolet light.

All of these results are exceptionally good when compared withFormulation G, containing a 7:1 ratio of ZnO to AgO, which retained onlyabout 63% of its initial whiteness value, after three days of exposureto ultraviolet light.

Example 62

Silver oxide formulations were prepared according to the generalprocedure provided in Example 48A. The active ingredients were:

-   -   silver(II) oxide (0.05% to 1.5%);    -   zinc oxide (1% to 11.3%);    -   at least one additional whitener or stabilization agent (1% to        9% magnesium hydroxide, calcium hydroxide, bentonite, calcium        carbonate, magnesium oxide, magnesium carbonate, or magnesium        sulfate).

Carrier ingredients were selected from beeswax, benzoic acid, bentonite,dimethicone, glycine, soybean oil, methylparaben, microcrystalline wax,mineral oil, panthenol, propylene glycol, propylparaben, sodiumhydroxide, sorbitan sesquioleate, tocopheryl acetate, and water. Aminute amount of fragrance was added to some of the formulations.

The silver(II) oxide based formulations generally exhibited an off-whiteor light gray appearance, suitable for topical formulations.

Example 63

Silver oxide formulations were prepared according to the generalprocedure provided in Example 48A. The active ingredients were:

-   -   silver(I) oxide (at least 0.1% to 3%);    -   zinc oxide (1% to 8%);    -   at least one additional whitener or stabilization agent (1% to        9% magnesium hydroxide, calcium hydroxide, bentonite, calcium        carbonate, magnesium oxide, magnesium carbonate, or magnesium        sulfate).

The carrier ingredients were substantially the same as those used inExample 16.

The silver(I) oxide based formulations generally exhibited an off-white,light gray, or medium gray appearance, suitable for topicalformulations.

Example 64

Silver oxide formulations were prepared according to the generalprocedure provided in Example 47. The active ingredients were:

-   -   silver(I) oxide or silver(II) oxide (0.05%);    -   zinc oxide (0.0375%);    -   magnesium oxide (0.01%; 0.0375%);

The carrier was the standard base described in Example 47. The ratio ofwhitener and stabilization agent to silver oxide was 0.2:1 and 0.75:1.The ratio of whitener (and stabilization agent to zinc oxide was 0.27:1and 1:1. The ratio of total whitener, zinc oxide and stabilization agentto silver oxide was 0.95:1 and 1.5:1. Under these conditions, both thesilver(I) and the silver(II) oxide based formulations exhibited agenerally off-white to slightly beige off-white appearance, suitable fortopical formulations.

Example 65

Silver oxide formulations were prepared according to the generalprocedure provided in Example 1. The active ingredients were:

-   -   silver(I) oxide or silver(II) oxide (0.01%);    -   zinc oxide (0.02%);    -   magnesium oxide (0.02%);

The carrier was the standard base described in Example 47. The ratio ofwhitener, zinc oxide and stabilization agent to silver oxide was 2:1.The ratio of whitener and stabilization agent to zinc oxide was 1:1. Asin Example 18, both the silver(I) and the silver(II) oxide basedformulations exhibited a generally off-white to slightly beige off-whiteappearance, suitable for topical formulations.

Example 66

Anti-microbial activity was evaluated indirectly using a Fishereducational spectrophotometer. This technique uses turbidity as anindicator of microbial growth. Bacterial samples were grown in aMuller-Hinton broth. Upon inoculation with the microbe, 4-5 mg samplesof the exemplary formulations were loaded on to a 6 mm sterile disc,dropped into the broth, and allowed to incubate for 24 hours. After apre-determined time, the samples were introduced to thespectrophotometer and the optical density (OD) measured. The OD reflectsthe turbidity of a sample, or the relative transparency of a sample tolight passing therethrough, to the light detector on the distal side.Increasing OD may be generally correlated with an increasedconcentration of microbes.

Example 67

Anti-microbial activity was evaluated using a Bel-Art Colony CountingSystem, Scienceware Colony Counting System Instrument. The colonycounting system may be performed instead of, or complementary to, theabove-described spectrophotometric method.

Bacterial samples were inoculated in Muller-Hinton broth and theanti-microbial formulations were loaded, as in the spectrophotometrictest described in Example 57. After 24 hours, a drop of the media wastaken and streaked on a Muller-Hinton agar plate. After the plates wereinoculated for 24 hours, the number of colonies visible in the plateswas counted. The number of colonies visible may be generally correlatedwith decreasing anti-microbial efficacy of the sample formulations.

Example 68

FIG. 15 is a bar graph showing the turbidity of a plurality of cultures,each culture containing a particular anti-microbial formulation. Oneculture is a control culture, having no anti-microbial components.Sample 1 has no whitener, and no stabilizing agent. Samples 2-9 allcontain an inorganic lightener or whitener. Some of theselighteners/whiteners may also act as a stabilizing agent that retardsthe discoloration process within the formulation.

All of the anti-microbial formulation containing cultures displayedpronounced anti-microbial activity. The least effective anti-microbialformulation was Sample 8, containing 1% Ag₂O and 7% TiO₂. The mosteffective anti-microbial formulations were Samples 3-5 and 8, allcontaining 1% Ag₂O and containing 7% of Ca(OH)₂, Mg(OH)₂, MgCO₃, or MgO,respectively.

TABLE 13 Sample ID# Sample Description Optical Density C Control 1.878 1AgO (1%) 0.898 2 AgO/CaCO₃ (1%, 7%) 0.876 3 AgO/Ca(OH)₂ (1%, 7%) 0.745 4AgO/Mg(OH)₂ (1%, 7%) 0.677 5 AgO/MgCO₃ (1%, 7%) 0.788 6 AgO/Bentonite(1%, 7%) 1.121 7 AgO/Ti₂O (1%, 7%) 1.232 8 AgO/MgO (1%, 7%) 0.656 9AgO/MgSO₄ (1%, 7%) 0.987

Example 69

FIG. 16 is a bar graph showing the colony counts for the anti-microbialformulation containing cultures of FIG. 15. The general trend is similarto the turbidity trend observed in Example 64. The most effectiveanti-microbial formulations were Samples 2-5, 8 and 9, all containing 1%Ag₂O and containing 7% of CaCO₃, Ca(OH)₂, Mg(OH)₂, MgCO₃, MgO, or MgSO₄,respectively. As in Example 66, the least effective anti-microbialformulation was Sample 8, containing 1% Ag₂O and 7% TiO₂.

TABLE 14 Sample ID# Sample Description Number of colonies 1 AgO (1%) 1652 AgO/CaCO3 (1%, 7%) 111 3 AgO/CaOH2 (1%, 7%) 123 4 AgO/MgOH2 (1%, 7%)98 5 AgO/MgCO3 (1%, 7%) 108 6 AgO/Bentonite (1%, 7%) 187 7 AgO/Ti2O (1%,7%) 211 8 AgO/MgO (1%, 7%) 117 9 AgO/MgSO4 (1%, 7%) 121

Another first aspect of the present invention relates to a solid orsubstantially solid formulation or medical device, typically having aputty-like consistency, which may be particularly efficacious as atopical antibiotic in various applications. Such formulations or medicaldevices may exhibit superior oxidative stability and superior phasestability, along with efficacy in the inhibition, treatment and cure ofvarious dermatological conditions. This formulation may be particularlyefficacious in the treatment of bedsores, diabetic ulcers such asdiabetic foot ulcers, puncture wounds, and the like.

The inventive putty formulation may include at least oneviscosity-building agent, typically including a hydrophilic clay orsmectite such as bentonite or hectorite, or an organoclay such as abentonite or hectorite organoclay, a humectant, typically including anoil or liquid wax ester such as jojoba oil, and a base liquid, typicallywater or an aqueous solvent. The formulation may advantageously includean absorbefacient.

The viscosity-building agent may include, largely include, predominantlyinclude, or consist essentially of a flour (such as wheat flour, cornflour, and/or rice flour) and/or a starch (such as corn starch or potatostarch).

The formulation may advantageously include, in addition to an antibioticagent, at least one preservative adapted to inhibit bacterial and/orfungal growth within the putty formulation. Preferably, thepreservative, or combination of preservatives, should be effectiveagainst bacteria, molds and yeasts. Such preservatives may include atleast one of benzoic acid, salicylic acid, and various parabens. Whilevarious preservatives are known to those of ordinary skill in the art ofcosmetic and pharmaceutical formulations, it will be appreciated thatthe chemical compatibility with silver(II) and silver(I) oxide must betested, for those formulations containing such silver oxides.

Preferred antibiotics may include at least one silver oxide. Preferably,the inventive solid or substantially solid formulation may include asilver(II) oxide such as tetrasilver tetroxide, or a silver(I) oxidesuch as Ag₂O or silver sulfadiazine. To benefit from the bacteriostaticand antibiotic properties of the silver(II) oxide, the formulation maycontain, by weight, at least 0.025% of the silver(II) oxide, and moretypically, at least 0.05%, at least 0.10%, at least 0.25%, or 0.25% to3.5 or 4% thereof. To benefit from the bacteriostatic and bacteriocidalproperties of the silver(I) oxide, the formulation may contain, byweight, at least 0.05% of the silver(I) oxide, and more typically, atleast 0.10%, at least 0.25%, or 0.25% to 3.5% thereof.

In topical applications such as the treatment of chronic wounds andacute wounds, the inventive formulation preferably exhibits particularmechanical, physical, bacteriocidal, palliative, moisturizing, andskin-protecting or skin-building properties. It is also essential thatthe various components of the formulation are biocompatible and arecompatible with one another.

In some applications, it may be essential for the inventive formulationto be highly absorbefacient, in order to dry up fluid serving as amedium for microbial growth. However, we have found that a delicatebalance may exist between inducing absorption and moisturization.Without a suitable moisturization agent or means, the absorption processmay disadvantageously dry up the surrounding tissue, which may promotetissue irritation and skin cracking and induce pain, discomfort, andeven additional infection. Moreover, we have found that the activity ofvarious antibiotic agents (e.g., silver(II) oxide) may be compromised indry environments, further constraining the balance between formulationabsorption and moisturization.

To this end, we have found that the putty or plaster formulation of thepresent invention may advantageously include at least about 1%, at leastabout 1.5%, at least about 2.5%, at least about 3%, at least about 4%,and preferably, about 4% to 55%, about 4% to 50%, about 4% to 45%, about5% to 40%, about 5% to 30%, or about 5% to 20%, by weight, of ahumectant such as a liquid wax ester and/or an oil. The humectant maytypically include, largely conclude, or consist mainly or predominantlyof, a liquid wax ester such as jojoba oil. Additional humectants will bereadily apparent to those of ordinary skill in the art.

The humectant may serve to mitigate or otherwise counter the dryingeffect of the absorbefacient. At higher concentrations of humectant, thehumectant may leak out, ooze out, or be otherwise discharged from theformulation, making the use of the formulation less clean and convenientfor medical practitioners and the patient.

Typically, the putty formulation may include at least about 2%, at leastabout 5%, at least about 8%, at least about 12%, or at least about 20%,by weight, and preferably, about 2% to 50%, about 3% to 45%, or about 4%to 40%, by weight, of at least one such absorbefacient. In theseconcentrations, the absorbefacient may serve a dual function as aviscosity-building agent. Various phyllosilicates or clays, includingsmectites, sepiolite and palygorskite, or organoclays such asdisteardimonium bentonite may advantageously behave both as anabsorbefacient and as a viscosity-building agent. The smectite mayinclude various natural and synthetic forms of bentonite,montmorillonite and hectorite. It may be appreciated by one of skill inthe art that hectorite may be somewhat more potent than bentonite andmontmorillonite as an absorbefacient and as a viscosity-building agent,on a per-weight basis, such that lower concentrations of hectorite maybe used to achieve the desired results. Those of ordinary skill in theart may readily identify other absorbefacient substances that may besuitable for use in the formulations according to the present invention.

It must be emphasized that the inventive formulation may betherapeutically effective in the treatment of wounds and skininfections, even without an antibiotic agent. Without wishing to bebound by theory, the inventors believe that the absorbefacient nature ofthe formulation is efficacious in reducing the moisture within the woundcavity, negatively impacting the growth environment of themicroorganisms.

The inventive putty formulation may further include a skin-protecting orskin-building agent. Typically, the formulation may advantageouslyinclude at least 0.2%, and more typically, 1% to 15% or 2% to 10%, byweight, of the skin-protecting or skin-building agent. One presentlypreferred agent is zinc oxide.

The solvent typically includes water. Water may constitute at least 2%,at least 5%, at least 10%, at least 25%, at least 35%, or at least 40%,by weight, of the inventive formulation, and more typically, about 40 or45% to 75%, or about 50% to 70% thereof.

We have discovered that with regard to various formulations of thepresent invention, a high weight ratio of the smectite (or moregenerally of the total weight of the at least one viscosity-buildingagent and absorbefacient) to the at least one antibiotic (e.g., Ag₂O, asilver(II) oxide such as tetrasilver tetroxide, or Bacitracin, Neomycinand the like) may not reduce the anti-microbial efficacy of theformulation. Weight ratios of up to 600:1 (smectite to antibiotic suchas silver(II) oxide), up to 250:1, up to 100:1, up to 50:1, or up to25:1 may display no decrease in anti-microbial efficacy (relative tosubstantially identical formulations having no smectite content) withrespect to various skin-related microorganisms.

In many formulations of the present invention, the weight ratio of thesmectite (or more generally of the total weight of the at least oneviscosity-building agent and absorbefacient) to the at least oneantibiotic is at least 0.2:1, at least 0.5:1, at least 1:1, at least2:1, at least 5:1, at least 10:1, at least 20:1, or at least 50:1.

Bentonite, montmorillonite and hectorite are presently preferredsmectites.

With particular regard to the putty formulations (including thick,viscous plaster formulations) of the present invention, the puttyformulation may have a weight ratio of at least one viscosity-buildingagent and absorbefacient (e.g., a smectite) to the at least oneantibiotic (e.g., silver(II) oxide) of at least 5:1, and more typically,about 5:1 to 200:1, about 5:1 to 75:1, or about 10:1 to 60:1.

In the putty formulation of the present invention, the weight ratio ofthe at least one viscosity-building agent and absorbefacient to at leastone humectant (e.g., jojoba oil) may be at least 0.25:1, at least 0.4:1,at least 0.6:1, at least 1:1, and more typically, about 1.5:1 to 5:1,about 2:1 to 5:1, or about 2:1 to 4:1.

The inventive putty formulation may have various rheological propertiesthat are particularly suited to various topical applications. Forexample, the putty may have an overall flexibility that is sufficient toenable molding of the putty to conform or largely conform to the shapeof various surfaces. For example, a cavity of a wound or bedsore may befilled or partially filled with the inventive putty, whereby the puttyconforms to the shape of the cavity. The putty may be inserted into thewound cavity as an integral piece, or as integral pieces. The putty mayexhibit sufficient rigidity or stiffness to maintain its position overtime (e.g., at least 1 hour, at least 2 hours, at least 4-12 hours, atleast 24 hours, at least 48 hours, or at least 72 hours), within such acavity, without oozing out, falling out, etc. The putty may exhibitsufficient rigidity or stiffness even as the temperature of the puttyincreases from room temperature to the temperature within the wound ofthe patient (human or animal).

The inventive putty formulation may advantageously be adapted to retainits integrity within the wound cavity, whereby the putty may be removedas an integral piece after at least 1 hour, at least 2 hours, at least 4hours, or even after at least 24-72 hours.

The putty formulation may be rheologically adapted to apply a gentleand/or constant pressure against the surrounding tissue. While suchpressure contact may promote improved contact between the antibioticagent and the microorganisms, the contact may, in medical devices andtechniques of the prior art, result in sticking of the medical device(e.g., gauze) to the wound surface. Absorbefacients pressure-contactedwith a wound surface may excessively dry out the surface. Such effectsmay adversely affect wound healing, and may subject the patient todiscomfort or acute pain. Absorbefacients pressure-contacted with thewound surface may also disintegrate or stick to the wound surface.

By sharp contrast, the inventive formulation may be adapted to remainintegral within the wound cavity, to pressure-contact the wound surfaceswithout sticking thereto, and to be removed with facility from thewound. The formulation may be loaded with sufficient humectant, wherebyexcessive drying out of the wound surface is avoided, even over severaldays of continuous presence within the wound cavity.

Various rheological properties of the inventive putty formulation, suchas viscosity and/or complex modulus (G*), may be generally maintainedbetween room temperature (about 20-22° C.) and body temperature (about32-35° C.). This may not be true for various materials or carriers basedon petroleum, by way of example. Thus, the formulation components may beselected, and the formulation may be prepared, whereby the meltingtemperature of the formulation as a whole, is at least 40° C., at least45° C., at least 50° C., or more typically, at least 75° C.

In characterizing the rheological properties of the present invention,we have found that the inventive formulation may have a large storagemodulus (G′) relative to the loss modulus (G″). Using a rotationalrheometer such as a TA Instruments G2 rotational rheometer, we havefound that the storage modulus, at any point or at substantially everypoint in the frequency range of 0.1 Hz to 1.0 Hz, may be at least0.2×10⁴ Pa, at least 0.5×10⁴ Pa, at least 1.0×10⁴ Pa, at least 2×10⁴ Pa,at least 3.0×10⁴ Pa, at least 4.0×10⁴ Pa, at least 6.0×10⁴ Pa, at least9.0×10⁴ Pa, or at least 12.0×10⁴ Pa. At any point or at substantiallyevery point in this frequency range, the storage modulus may be lessthan 1.2×10⁷ Pa, less than 1.0×10⁷ Pa, less than 8×10⁶ Pa, or less than7×10⁶ Pa. More typically, the storage modulus may be within a range of3.0×10⁴ Pa to 1.0×10⁷ Pa, within a range of 3.5×10⁴ Pa to 9×10⁶ Pa,within a range of 4.0×10⁴ Pa to 7×10⁶ Pa, or within a range of 5.0×10⁴Pa to 7×10⁶ Pa.

In further characterizing these structural rheological properties, wehave found that, at any point or at substantially every point in thefrequency range of 0.1 Hz to 1.0 Hz, the loss modulus of the inventiveputty formulation may be at least 0.1×10⁴ Pa, at least 0.4×10⁴ Pa, atleast 0.5×10⁴ Pa, at least 0.6×10⁴ Pa, at least 0.8×10⁴ Pa, or at least1.0×10⁴ Pa. At any point or at substantially every point in thisfrequency range, the loss modulus may be less than 5×10⁶ Pa, less than3×10⁶ Pa, less than 2×10⁶ Pa, or less than 1×10⁶ Pa.

The ratio of the storage modulus to the loss modulus, at any point or atsubstantially every point in the frequency range of 0.1 Hz to 1.0 Hz,may be at least 1.0:1, at least 1.5:1, at least 2.0:1, at least 2.5:1,at least 3:1, at least 4:1, or at least 5:1. This ratio may be less than12:1, less than 10:1, less than 9:1, or less than 8:1. The ratio of thestorage modulus to the loss modulus may be in a range of 2.5:1 to 12:1,3:1 to 10:1, or 4:1 to 9:1. Some formulations of the present inventionhave a storage modulus to loss modulus ratio of 4.5:1 to 7.5:1, or 5:1to 7:1.

The complex modulus (G*), which is defined by the equation:G*=(G′ ² +G″ ²)^(1/2)

may be, at any point or at substantially every point in this frequencyrange, at least 0.3×10⁴ Pa, at least 0.5×10⁴ Pa, at least 0.7×10⁴ Pa, atleast 1.0×10⁴ Pa, at least 2×10⁴ Pa, at least 3.0×10⁴ Pa, or at least4.0×10⁴ Pa, at least 6.0×10⁴ Pa, at least 9.0×10⁴ Pa, at least 12.0×10⁴Pa, or at least 12.0×10⁴ Pa. At any point or at substantially everypoint in this frequency range, the complex modulus may be less than1.2×10⁷ Pa, less than 1.0×10⁷ Pa, less than 8×10⁶ Pa, or less than 7×10⁶Pa. More typically, the complex modulus may be within a range of 1.0×10⁴Pa to 1.0×10⁷ Pa, within a range of 2.0×10⁴ Pa to 1.0×10⁷ Pa, within arange of 3.0×10⁴ Pa to 1.0×10⁷ Pa, within a range of 3.5×10⁴ Pa to 9×10⁶Pa, or within a range of 4.0×10⁴ Pa to 7×10⁶ Pa.

At at least one point within the frequency range, the ratio of thestorage modulus to the loss modulus is at least 1.5:1, at least 2.0:1,at least 2.5:1, at least 3:1, at least 4:1, or at least 5:1, and/or theratio is less than 12:1, less than 10:1, less than 9:1, or less than8:1.

Example 70

To a container containing water or more generally, an aqueous medium, isadded at least one viscosity-building agent, typically a smectite (e.g.,a bentonite or montmorillonite powder such as Gelwhite H, produced bySouthern Clay Products, Inc., Gonzales, Tex.). The mixture is vigorouslymixed or homogenized, typically for 0.5 to 2 hours, typically producinga single, viscous phase. The phase is typically homogeneous orsubstantially homogeneous. The oil and/or liquid wax ester (e.g., jojobaoil) may be introduced to the mixture during the mixing (e.g., blendingor homogenizing), typically after the viscosity has been built. Mixingmay be continued as the antibiotic (e.g., tetrasilver tetroxide) andvarious optional ingredients (e.g., skin builders) are introduced.Further mixing may ensue, typically for 5-30 minutes. Viscosity-buildingagents such as flours and starches may be introduced towards the end ofthe preparation process; a dough hook may advantageously be used for thesubsequent mixing. The viscous formulation is typically homogeneous orsubstantially homogeneous.

Example 71

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained included approximately 66% water, 24%bentonite, 9% jojoba oil, and 0.88% tetrasilver tetroxide.

Example 72

A putty formulation was prepared according to the procedure provided inExample 70 The putty contained included approximately 65% water, 23%bentonite, 9% jojoba oil, 2% zinc oxide, and 0.88% tetrasilvertetroxide.

Example 73

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained approximately 53% water, 37% bentonite,9% jojoba oil, and 0.88% tetrasilver tetroxide.

Example 74

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained 53% water, 35% bentonite, 9% jojoba oil,2% zinc oxide, and 0.88% tetrasilver tetroxide.

Example 75

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained approximately 41% water, 3.4% bentonite,14.2% jojoba oil, 41% flour, and 0.5% tetrasilver tetroxide. The puttywas highly pliable and exhibited excellent phase stability.

Example 76

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained approximately 47% water, 10% bentonite,43% jojoba oil, and under 0.1% tetrasilver tetroxide. The puttyformulation was designated as Sample 11010-1.

Example 77

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained approximately 46% water, 34% bentonite,13% jojoba oil, 5% zinc oxide, and 1% tetrasilver tetroxide. The puttyformulation was designated as Sample 11010-2.

Examples 78-79

The putty formulations of Example 76 and Example 77 were subjected torheological evaluation using a TA Instruments G2 rotational rheometer.

Small amplitude oscillatory rheometry was conducted on the providedsamples, using a two-centimeter, stainless steel parallel plategeometry. To overcome sample-loading issues, the two samples were placedon the Peltier plate of the rheometer, and partially flatted with a flatTeflon® plate. Two one-millimeter shims were placed on either side ofthe sample, and a doctor blade was used to trim the sample toapproximately 1000 micrometers. The two-centimeter parallel plate wasthen lowered onto the sample, achieving a gap distance between 1000 and1050 micrometers.

The samples were initially subjected to a stress sweep at 1 Hz toidentify the suitable oscillating torque for the frequency sweep basedon waveform shape and the onset of non-linear viscoelastic behavior.Based on this work, a torque of 1000 μN-m was used for 11010-1, and 8000μN-m for 11010-2.

Frequency sweeps were then conducted on both samples from 0.01 to 100 Hzat 25° C. and the indicated oscillating torques. Ten points werecollected per decade of oscillating frequency. The run for sample11010-1 showed inertial effects at frequencies above 16 Hz; as such, thedata curve was truncated.

Both samples exhibit strongly elastic behavior in the regime tested,indicated by a large storage modulus G′ relative to the loss modulus G″.Sample 11010-1 is substantially less stiff than 11010-2 by approximatelya factor of 60-70. At 1 Hz, sample 11010-1 had a storage modulus of6.26×10⁴ Pa, while sample 11010-2 had a storage modulus of 4.32×10⁶ Pa.Both samples show a modest onset of a terminal zone at a frequency ofapproximately 0.03 Hz, followed by a quasi-plateau modulus. No strainhardening was observed in the achievable upper range of frequenciestested.

The complex modulus, G*, is the resultant vector of the storage and lossmodulus. A higher complex or overall modulus indicates a stiffermaterial, requiring more force to deform the material a set amount. Amaterial with a higher storage modulus relative to the loss modulus ismore elastic and will therefore recover more than a material with acloser ratio; the ratio of the loss (G′) to storage (G′) modulus isreported as tan δ. A purely elastic material would have a tan δ=0, whilea purely viscous material would have tan δ=∞. The comparison of theseparameters at two frequencies is shown in Table 15.

Consistent with the discussion above, there is a large difference inmodulus between samples 11010-1 and 11010-2, but only a modest frequencydependence in either sample. Also, the tan δ values are quite closebetween the two samples, indicating a similar relative level ofelasticity, albeit requiring different levels of force to achieve thesame degree of deformation. Both samples show a modest decrease in tanδ, indicating both materials become slightly more elastic withincreasing frequency. It should be noted that this test subjects thesample to small amplitudes of deformation; larger degrees of deformationcould require different levels of force, hence resulting in a differentmodulus, but the test implicitly assumes that the experiment isperformed in the linear viscoelastic regime of the material.

With regard to samples 11010-1 and 11010-2, the storage modulus G′ andthe loss modulus G″ are plotted in FIG. 17 and FIG. 18, respectively, asa function of frequency (“Frequency Sweep”). The values of G′, G″ and G*at 0.1 Hz and at 1.0 Hz are provided in Table 15 hereinbelow.

TABLE 15 Frequency Sample [Hz] G′ [Pa] G″ [Pa] G* [Pa] tan delta (δ)11010-1 0.1 5.37E+04 1.25E+04 5.51E+04 0.23 1.0 6.26E+04 1.03E+046.34E+04 0.17 11010-2 0.1 3.45E+06 6.92E+05 3.52E+06 0.20 1.0 4.32E+065.99E+05 4.36E+06 0.14

Example 80

A putty formulation was prepared according to the procedure provided inExample 70. The putty contained 42.5% water, 3.3% bentonite, 13.8%jojoba oil, 39.9% flour, and 0.5% tetrasilver tetroxide. The putty wassoft and slightly sticky, relative to the formulation of Example 75, butexhibited both high pliability and excellent phase stability.

Example 81

The putty formulation of Example 80 was subjected to rheologicalevaluation using a TA Instruments ARG2 rheometer.

Small amplitude oscillatory rheometry was conducted on the providedsamples using a TA Instruments ARG2 rheometer. A two-centimeter,stainless steel parallel plate geometry was used to prevent the bridgingeffects that can occur in cone geometries when particle sizes might besignificant. A gap of 1000 microns was used.

The samples were initially subjected to a torque sweep at 1 Hz toidentify the suitable oscillating torque for the frequency sweep basedon waveform shape and the onset of non-linear viscoelastic behavior.Based on this work, a torque of 1000 μN-m was determined.

A frequency sweep was then conducted on the sample, from 0.01 to 100 Hzat 25° C., using the oscillating torque amplitudes described above. Tenpoints were collected per decade of frequency.

The results from the torque sweep are shown in FIG. 19. The sampleshowed non-linear behavior at approximately 2,000 Pa.

The frequency sweep data are plotted in FIG. 20. The sample exhibited afairly flat modulus behavior, indicating little dependency on frequency.

This data is summarized at 3 frequencies (0.1 Hz, 1.0 Hz, and 10 Hz) inTable 16. The behavior of the sample was predominantly elastic, with thecomplex modulus ranging from about 1×10⁵ to 2×10⁵ Pa.

TABLE 16 Frequency Sample [Hz] G′ [Pa] G″ [Pa] G* [Pa] tan delta (δ)11264-2 0.1 1.29E+05 3.08E+04 1.33E+05 0.24 1.0 1.60E+05 2.12E+041.61E+05 0.13 10 1.70E+05 1.57E+04 1.71E+05 0.09

Example 82

A formulation was prepared according to the procedure provided inExample 70, containing 69.8% water, 9.3% bentonite, 8.1% jojoba oil,9.3% flour, 3% zinc oxide, and 0.5% tetrasilver tetroxide. Theformulation was soft, having a soft putty or plaster-like consistency,and exhibited both high pliability and excellent phase stability.

Example 83

A formulation was prepared according to the procedure provided inExample 70, containing 68.5% water, 18.3% bentonite, 7.9% jojoba oil,4.8% zinc oxide, and 0.5% tetrasilver tetroxide. The formulation wassoft, having a plaster-like consistency and exhibited both highpliability and excellent phase stability.

Example 84

The formulation of Example 82 was prepared according to the generalprocedure provided in Example 70, however, the mixing of the bentoniteinto the water was conducted for about 10 minutes. Despite having acomposition substantially identical to that of Example 82, theformulation failed to develop the requisite viscosity or body. Theformulation had a paste-like consistency, even after additional mixingtime was provided after the silver oxide and zinc oxide were introduced.

Example 85

A formulation was prepared according to the procedure provided inExample 70, containing 65.4% water, 11.3% bentonite, 17.8% jojoba oil,5% zinc oxide, and 0.5% tetrasilver tetroxide. The formulation was soft,exhibiting a plaster-like consistency and exhibited both high pliabilityand excellent phase stability.

Example 86

A putty formulation was prepared according to the procedure provided inExample 70, containing 40.6% water, 3.4% bentonite, 14.2% jojoba oil,40.5% wheat flour, 0.5% tetrasilver tetroxide, 0.5% Allantoin, 0.1%Benzathonium Cl, and 0.5% Lidocaine.

Example 87

A putty formulation was prepared according to the procedure provided inExample 70, containing 39.0% water, 3.1% bentonite, 13.5% jojoba oil,40.0% wheat flour, 0.5% tetrasilver tetroxide, 1.0% Clotrimazole, 5%salicyclic acid, and 0.1% colloidal oatmeal.

Example 88

The anti-microbial efficacy of various formulations was tested andcompared using a Kirby-Bauer type test, as follows:

Ready-made Muller-Hilton agar was streaked with the bacterial inoculumusing a sterile applicator. The sample was allowed to sit for 5 minutesto ensure that the bacteria adhere to the surface of the agar.Subsequently, an antibiotic sterile blank disc was pressed against aknown quantity of the formulation being tested. Multiple duplicate discswere used to verify the data. The disc was pressed against the surfaceof the agar, making sure not to damage the disc or the agar. Each agarplate was then inverted and allowed to sit in the incubator at 37° C.for 24 hours. The plates were subsequently removed from the incubator,and the zone of inhibition was measured using a ruler.

The anti-microbial efficacy of eight formulations was tested andcompared using the procedure detailed above, using Enterococcusfaecalis.

Formulation Nos. 1-7 correspond to the formulations produced in ExampleNos. 75, 80, 82, 83, 85, 86, and 87. Formulation No. 8 was a controlformulation, produced according to the procedure outlined in Example 70.The control formulation was a putty containing: 40% water, 3.4%bentonite, 14.2% jojoba oil, and 40% wheat flour. No antibiotic wasincluded in the control formulation.

The zone of inhibition for the control formulation was substantially 0mm. By sharp contrast, the zone of inhibitions for Formulation Nos. 1-7all fell within a narrow range of about 12-14 mm (see FIG. 21). Such alarge zone of inhibition may be considered a clear manifestation of theappreciable antibiotic activity of the inventive formulations, and wasobtained using a low concentration of the silver oxide. Moreover, thelarge zone of inhibition may be especially noteworthy in view of theextremely high viscosities exhibited by the inventive puttyformulations.

Examples 89-95

Formulations having compositions generally along the lines of Example80, were prepared according to the procedure provided in Example 70. InExample 89, the putty contained 42.5% water, 3.3% bentonite, 13.8%jojoba oil, 39.9% flour, and 0.5% tetrasilver tetroxide, as in Example11. The flour was a whole wheat flour. The putty was soft and slightlysticky, relative to the formulation of Example 75 but exhibited bothhigh pliability and moldability, and excellent phase stability.

In Example 90, rice bran flour replaced the wheat flour, and thesilver(II) oxide concentration was increased to 4%. To obtain a similarconsistency as that obtained in Example 89, the ratio of filler (riceflour) to water was increased from 0.94 to 1.48, representing a 58%increase in filler, relative to the wheat flour of Example 89. The puttyhad a dark gray color, which may largely be due to the relatively highconcentration of the silver(II) oxide. The putty was soft and slightlysticky, relative to the formulation of Example 75 and exhibitedexcellent phase stability. The formulation had a somewhat grainyappearance and was moldable, though less so than the putty of Example89.

In Example 91, corn starch replaced the wheat flour of Example 89, whilethe silver(II) oxide concentration was maintained at 0.5%. To obtain asimilar consistency as that obtained in Example 89, the ratio of filler(corn starch) to water was increased from 0.94 to 1.09, representing a17% increase in filler, relative to the wheat flour of Example 89. Theputty had a substantially white appearance. The putty was soft andslightly sticky, relative to the formulation of Example 75, andexhibited excellent phase stability. The formulation was moldable,though less so than the putty of Example 89.

In Example 92, potato starch replaced the wheat flour of Example 89,while the silver(II) oxide concentration was increased at 1.5%. Toobtain a similar consistency as that obtained in Example 89, the ratioof filler (potato starch) to water was increased from 0.94 to 1.25,representing a 33% increase in filler, relative to the wheat flour ofExample 89. The putty had a yellow tinge. The putty was soft andslightly sticky, relative to the formulation of Example 6, and exhibitedexcellent phase stability. The formulation was more grainy than theputty of Example 91 and was moldable, though less so than the putty ofExample 89.

In Example 93, the whole wheat flour of Example 89 was used, but thesilver(II) oxide was replaced by silver(I) oxide (0.5%). The appearanceof the putty, consistency, and phase stability appeared to be identical,or substantially identical to those of the putty of Example 89.

In Examples 94 and 95 the putty formulation of Example 89 was prepared,again, according to the general procedure of Example 70. In eachformulation, a different topical antibiotic material was used instead ofthe silver(II) oxide. The concentration of each antibiotic material wasselected according to the concentration of the antibiotic material incommercially available ointments. Thus, in Example 94, the antibioticmaterial was clotrimazole, 1% by weight; in Example 95, the antibioticmaterial was erythromycin, 2% by weight. The appearance, consistency,and phase stability of the putties of Example 94 appeared to beidentical, or substantially identical to those of the putty of Example89.

Example 96

Fifty four patients were treated at Irvine3 Circulation/Vascular Labs(Chieti-Pescara University, Pescara, Italy). Patients were matched withother patients of similar age and similar general health condition, andhaving complex ulcers of similar type, size and severity. Effectively,18 groups of three patients were formed for the purpose of comparativetesting.

Within each group of three, a first patient was treated withconventional cleaning and compression management methods. A secondpatient within each group was treated with an ointment, containingapproximately 0.9% silver(II) oxide and 6.8% ZnO in a beeswax and jojobaoil base. The ointment was applied around and at the edge of theulcerated areas and on the ulceration, following the identicalconventional cleaning methods used on the first patient.

The third patient within each group was treated with anantibiotic-containing putty of the present invention. The antibiotic,consisting essentially of tetrasilver tetroxide (silver(II) oxide), wasdispersed within the putty, which had the composition of the puttydescribed in Example 75, and was prepared according to the procedureprovided in Example 70.

FIG. 22 provides bar graphs showing the wound closure data from each ofthe 18 comparative clinical trials. In FIG. 22, associated with eachtrial number are three juxtaposed bar graphs, the right-most of whichrepresents the patient subjected to the conventional treatment, themiddle bar graph represents the patient treated with the ointmentcontaining the silver(II) oxide, and the left-most of which representsthe patient treated using the formulation of the present invention.

On average, the complex ulcers treated by conventional means requiredover 31 days to close, on average. The complex ulcers treated with thesilver(II) oxide based ointment required almost 17 days to close, onaverage, an appreciable improvement over the results for the controlgroup. The complex ulcers treated with the antibiotic-containing puttyof the present invention closed after just over 10.1 days, on average,about ⅓ of the time required for the wounds of the control group, andabout 40% less time with respect to the excellent result achieved usingthe ointment. The performance of the inventive antibiotic putty is moresurprising in view of the relatively low concentration of antibiotic(0.5% silver(II) oxide) in the putty, with respect to the concentrationof the same antibiotic (˜0.9% silver(II) oxide) in the antibioticointment formulation. The improved performance is even more surprisingin view of past experience showing that for a given concentration ofantibiotic material, more viscous formulations may considerably lessefficacious from a bacteriocidal standpoint.

As used herein in the specification and in the claims section thatfollows, the term “antibiotic” refers to a substance that selectivelyattacks and destroys at least one species or type of microorganism,while exhibiting relative inertness with respect to human and/ormammalian cells. More typically the antibiotic substance selectivelyattacks and destroys at least one species or type of microorganism thatcommonly populates the skin, surface wounds, bedsores and the like,while exhibiting relative inertness, with respect to skin cells ofhumans and/or mammals. The term “antibiotic” is specifically meant toexclude anti-microbial preservatives, both anti-fungal preservatives andanti-bacterial preservatives. Such anti-fungal preservatives include,but are not limited to, compounds such as benzoic and ascorbic acids andsalts thereof, and phenolic compounds such as methyl, ethyl, propyl andbutyl p-hydroxybenzoate (parabens). Antibacterial preservatives include,but are not limited to, compounds such as quaternary ammonium salts,alcohols, phenols, mercurials and biguanidines. The term “antibiotic” isspecifically meant to exclude anti-microbial preservatives such as tablesalt and the like, vinegar, sodium nitrate, sodium nitrite, andsulfites. The term “antibiotic” is specifically meant to include,without being limited to, silver oxides such as silver(I) oxide andsilver(II) oxide, silver sulfadiazine, and any other topical antibioticsthat are efficacious in the treatment of serious skin wounds such asbedsores, skin ulcers, and puncture wounds, or that are efficacious inthe treatment of mundane skin wounds. The term “antibiotic” isspecifically meant to include “classic” topical antibiotics such asBacitracin, Neomycin, Erythromycin and Chloramphenicol. Additionaltopical antibiotic substances may be readily apparent to those ofordinary skill in the art.

As used herein in the specification and in the claims section thatfollows, the term “therapeutically effective amount”, with respect to anantibiotic substance or formulation, refers to a quantity that producesa positive result in the treatment of at least one topical infection.

As used herein in the specification and in the claims section thatfollows, the term “therapeutically effective concentration”, withrespect to an antibiotic substance within a formulation or medicaldevice, refers to a concentration of the antibiotic, within theformulation or medical device, which produces a positive result in thetreatment of at least one topical infection.

As used herein in the specification and in the claims section thatfollows, the term “putty”, with respect to a substance or formulation,is meant to refer solely to the physical consistency of the substance orformulation.

As used herein in the specification and in the claims section thatfollows, the term “plaster”, with respect to a substance or formulation,is meant to refer solely to the physical consistency of the substance orformulation.

As used herein in the specification and in the claims section thatfollows, the term “silver (II) oxide” refers to a silver oxide whoseunit structure contains silver and oxygen in a substantially 1:1 molarratio. The term “silver (II) oxide” is specifically meant to includeAg₄O₄ (often represented as Ag₂O₃.Ag₂O) and AgO.

As used herein in the specification and in the claims section thatfollows, the term “whiteness value” may be represented by a luminanceparameter L*, as specified by the International Commission onIllumination (Commission Internationale d'Eclairage, or CIE), andexpressed as a percentage, wherein L*=0 represents black, and L*=100represents diffuse white.

As used herein in the specification and in the claims section thatfollows, the term “whiteness value” or “reflectance value”, with respectto a substance or formulation, may be represented by a reflectancevalue, in reflectance units, as determined by a LabScan XEspectrophotometer instrument (HunterLab, VA), or the like. Thespectrophotometer must be calibrated whereby the measured reflectancevalue of the following sample substances, is within 0.40 reflectanceunits, and preferably within 0.30 reflectance units or 0.20 reflectanceunits, of the respective measured reflectance values provided below:

Measured Cyan Magenta Yellow Key Observed Reflectance Sample ID (C) (M)(Y) (K) Color Units (RU) Sample A1 7 3 2 11 Light gray 5.21 Sample A2 23 4 5 Light gray 5.67 Sample A3 17 12 20 24 Medium gray 4.12 Sample A422 14 9 31 Medium gray 4.55 Sample A5 16 23 23 69 Dark gray 3.49

Typically, a light gray formulation exhibits a reflectance of at leastabout 4.8 RU; a medium gray formulation exhibits a reflectance in arange of about 3.8 to about 4.8 RU; a dark gray formulation exhibits areflectance of less than about 3.8 RU, and typically between about 1.0and 3.8 RU or between 2.0 and 3.8 RU.

As used herein in the specification and in the claims section thatfollows, the term “laundered white cloth” and the like refers to a whitecloth swatch that has been stained and laundered substantially accordingto the staining and laundering procedure described hereinabove.

As used herein in the specification and in the claims section thatfollows, the term “initial whiteness value” with respect to a substanceor formulation, refers to the whiteness value of the substance orformulation, prior to significant exposure to ultraviolet radiation.Typically, the initial whiteness value is measured within severalminutes, or within an hour, from the time the substance or formulationis dispensed from its tube, vial, or the like.

As used herein in the specification and in the claims section thatfollows, the term “gray hue” and the like, with respect to a substanceor formulation, is meant to include light gray, medium gray, dark gray,and off-white hues.

As used herein in the specification and in the claims section thatfollows, the term “stabilization agent” and the like, refers to asubstance that retards or otherwise reduces the darkening of silveroxide formulations over time or over exposure to ultraviolet light. Theterm “stabilization agent” is meant to specifically exclude titania andzinc oxide.

As used herein in the specification and in the claims section thatfollows, the term “constant exposure to ultraviolet light” and the likerelates to conditions identical or substantially identical to thosedelineated in Example 10, or to conditions determined and demonstratedby an expert in the art to yield identical or highly similar resultswith respect to the conditions delineated in Example 10.

As used herein in the specification and in the claims section thatfollows, the term “percent”, or “%”, refers to percent by weight, unlessspecifically indicated otherwise.

Similarly, the term “ratio”, as used herein in the specification and inthe claims section that follows, refers to a weight ratio, unlessspecifically indicated otherwise.

As used herein in the specification and in the claims section thatfollows, the term “largely includes”, with respect to a component withina formulation, refers to a weight content of at least 30%.

As used herein in the specification and in the claims section thatfollows, the term “mainly includes”, with respect to a component withina formulation, refers to a weight content of at least 50%.

As used herein in the specification and in the claims section thatfollows, the term “predominantly includes”, with respect to a componentwithin a formulation, refers to a weight content of at least at least65%.

It will be appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, mayalso be provided in combination in a single embodiment. Conversely,various features of the invention, which are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any suitable sub-combination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

What is claimed is:
 1. A method of providing a biocompatible puttywithin a skin wound cavity of a patient, the method comprising: (a)providing the biocompatible putty, the biocompatible putty including:(i) a biocompatible humectant, (ii) a biocompatible viscosity-buildingagent, and (iii) a topical antibiotic including a silver oxide; saidbiocompatible humectant and said biocompatible viscosity-building agentbeing intimately mixed; the biocompatible putty formulated and adaptedwhereby the biocompatible putty remains in putty form over at least anentire temperature range of 20° C. to 35° C.; (b) introducing a plug ofthe biocompatible putty into the skin wound cavity; (c) contacting asurface of the skin wound cavity with said plug; and (d) following saidcontacting, removing said plug, in an integral fashion, from the skinwound cavity; wherein a melting temperature of the formulation is atleast 50° C.
 2. The method of claim 1, further comprising maintaining ofsaid contacting for at least 4 hours, prior to said removing said plug,in said integral fashion, from the skin wound cavity.
 3. The method ofclaim 2, said maintaining of said contacting being performed for atleast 12 hours.
 4. The method of claim 1, said contacting of saidsurface of the skin wound cavity being performed so as to securely holdsaid plug in position within the skin wound cavity.
 5. The method ofclaim 1, the skin wound cavity being selected from the group consistingof bedsores; and diabetic ulcers.
 6. The method of claim 1, thebiocompatible putty further including at least 0.3%, by weight, of askin-protecting agent.
 7. The method of claim 1, the biocompatible puttyfurther including at least 5%, by weight, water.
 8. The method of claim1, the biocompatible putty further including at least 40%, by weight,water.
 9. The method of claim 1, said silver oxide including asilver(II) oxide.
 10. The method of claim 1, the biocompatible puttyfurther including an absorbefacient.
 11. A method of providing abiocompatible putty within a skin wound cavity of a patient, the methodcomprising: (a) providing the biocompatible putty, the biocompatibleputty including: (i) a biocompatible humectant, and (ii) a biocompatibleviscosity-building agent, and said biocompatible humectant and saidbiocompatible viscosity-building agent being intimately mixed; thebiocompatible putty formulated and adapted whereby the biocompatibleputty remains in putty form over at least an entire temperature range of20° C. to 35° C.; (b) introducing a plug of the biocompatible putty intothe skin wound cavity; (c) contacting a surface of the skin wound cavitywith said plug; and (d) after said contacting, removing said plug, in anintegral fashion, from the skin wound cavity; wherein saidviscosity-building agent includes at least 30%, by weight, of at leastone of a hydrophilic clay, a flour, and a starch wherein a meltingtemperature of the formulation is at least 75° C.
 12. The method ofclaim 11, further comprising maintaining of said contacting for at least4 hours.
 13. The method of claim 11, wherein said viscosity-buildingagent consists essentially of at least one of said hydrophilic clay,said flour, and said starch.
 14. The method of claim 1, wherein saidviscosity-building agent includes at least 30%, by weight, of at leastone of a hydrophilic clay, a flour, and a starch.
 15. The method ofclaim 1, wherein a melting temperature of the formulation is at least75° C.
 16. The method of claim 11, the biocompatible putty furtherincluding a topical antibiotic, said topical antibiotic including 0.25%to 4% silver oxide.
 17. A method of providing a biocompatible puttywithin a skin wound cavity of a patient, the method comprising: (a)providing the biocompatible putty, the biocompatible putty including:(i) a biocompatible humectant, (ii) a biocompatible viscosity-buildingagent, and (iii) a topical antibiotic including a silver oxide; saidbiocompatible humectant and said biocompatible viscosity-building agentbeing intimately mixed; the biocompatible putty formulated and adaptedwhereby the biocompatible putty remains in putty form over at least anentire temperature range of 20° C. to 35° C.; (b) introducing a plug ofthe biocompatible putty into the skin wound cavity; (c) contacting asurface of the skin wound cavity with said plug; and (d) after saidcontacting, removing said plug, in an integral fashion, from the skinwound cavity; wherein said viscosity-building agent includes at least30%, by weight, of at least one of a hydrophilic clay, a flour, and astarch; wherein said silver oxide includes at least 0.10% silver(II)oxide; and wherein said viscosity-building agent includes at least 30%,by weight, of said hydrophilic clay, said hydrophilic clay beingselected from at least one of the group consisting of a smectite,sepiolite, and palygorskite.
 18. The method of claim 2, said maintainingof said contacting being performed for at least 24 hours.
 19. The methodof claim 1, further comprising, after said contacting, removing saidplug, in an integral fashion, from the skin wound cavity, and prior tosaid removing, fitting said plug to a contour of the skin wound cavity.